EP1532164A1 - Template-fixed peptidomimetics with antibacterial activity - Google Patents

Template-fixed peptidomimetics with antibacterial activity

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Publication number
EP1532164A1
EP1532164A1 EP02779268A EP02779268A EP1532164A1 EP 1532164 A1 EP1532164 A1 EP 1532164A1 EP 02779268 A EP02779268 A EP 02779268A EP 02779268 A EP02779268 A EP 02779268A EP 1532164 A1 EP1532164 A1 EP 1532164A1
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Prior art keywords
lower alkyl
chr
alkenyl
alkyl
conr
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EP02779268A
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German (de)
French (fr)
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EP1532164B1 (en
Inventor
Jan Wim Vrijbloed
Daniel Obrecht
John Anthony Robinson
Odile Sellier
Marc Kessler
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Universitaet Zuerich
Spexis AG
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Universitaet Zuerich
Polyphor AG
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    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
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    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • A—HUMAN NECESSITIES
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    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention provides template-fixed ⁇ -ha ⁇ rp ⁇ n peptidomimetics incorporating a template- fixed chain of 12 ⁇ -amino acid residues which, depending on their positions in the chain, are Gly or Pro, or of certain types, as defined herein below These template-fixed ⁇ -hairpin mimetics have a selective antimicrobial activity
  • the present invention provides efficient synthetic processes by which these compounds can, if desired, be made in parallel library-format
  • These ⁇ - hairpin peptidomimetics show improved efficacy, bioavailability, half-life and most importantly a significantly enhanced ratio between antibacterial activity on the one hand, and hemolysis of red blood cells on the other
  • catiomc peptides such as protegrin 1 (A Aumelas, M Mangoni, C Roumestand, L Chiche, E Despaux, G Grassy, B Calas, A Chavanieu, A Eur J Biochem 1996, 237, 575-583, R L Fahrner, T Dieckmann, S S L Harwig, R I Lehrer, D Eisenberg, J Feigon, J Chem Biol 1996, 3, 543-550) and tachyplesin I (K Kawano, T Yoneya, T M ⁇ yata, K Yoshikawa, F Tokunaga, Y Terada, S J Iwanaga, S J Biol Chem 1990
  • a key issue in the design of new selective catiomc antimicrobial peptides are bioavailability, stability and reduced haemolytic activity
  • the naturally occurring protegrms and tachyplesins exert a significant hemolytic activity against human red blood cells This is also the case for protegrin analogues such as IB367 (J Chen, T J Falla, H J Liu, M A Hurst, C A Fujn, D A Mosca, J R Embree, D J Loury, P A Radel, C C Chang, L Gu, J C Fiddes, Biopolymers 2000, 55, 88-98, C Chang, L Gu, J Chen, US-Pat 5,916,872, 1999)
  • This high hemolytic activity essentially obviates its use in vivo, and represents a serious disadvantage in clinical applications
  • the antibiotic activity of analogues often decreases significantly with increasing salt concentration, such that under in vivo conditions (ca 100-150 mM NaCl) the antimicrobial activity may be severely reduced
  • protegrin 1 exhibits potent and similar activity against gram-positive and gram-negative bacteria as well as fungi in both low- and high-salt assays This broad antimicrobial activity combined with a rapid mode of action, and their ability to kill bacteria resistant to other classes of antibiotics, make them attractive targets for development of clinically useful antibiotics
  • the activity against gram- positive bacteria is typically higher than against gram-negative bacteria
  • protegrin 1 also exhibits a high hemolytic activity against human red blood cells, and hence a low selectivity towards microbial cells Oriented CD experiments (W T Heller, A J Waring, R I Lehrer, H W Huang, Biochemistry 1998, 37, 17331-17338) indicate that protegrin 1 may exist in two different states as it interacts with membranes, and these states are strongly influenced by lipid composition
  • Studies of cyclic protegrin analogues J -P Tam, C Wu, J -L Yang, Eur J Biochem 2000, 267, 3289-3300 have revealed, that an increase in the conformational rigidity
  • Protegrin I is an 18 residues linear peptide, with an amidated carboxyl terminus and two disulfide bridges Tachyplesin I contains 17 residues, also has an amidated carboxyl terminus and contains two disulfide bridges
  • Recently described backbone-cyclic protegrin and tachyplesin analogues typically contain 18 residues and up to three disulfide bridges (J P Tam, C Wu, J -L Yang, Eur J Biochem 2000, 267, 3289-3300, J P Tam, Y -A Lu, J -L Yang, Biochemistry 2000, 39, 7159-7169, N Sitaram, R Nagara ⁇ j, -3.oc .ew Biophys Res Comm 2000, 267, 783-790)
  • C ⁇ thehcidin a 37-res ⁇ due linear helical-type catiomc peptide, and analogues are currently under investigation as inhaled therapeutic agents for cystic fibrosis (CF) lung disease
  • CF cystic fibrosis
  • Over 80% of CF patients become chronically infected with pseudomonas aeruginosa C A Demko, P J Biard, P B Davies. Clin Epidemiol 1995, 45, 1041-1049, E M Kerem, R Gold, H Lev ⁇ nson, J Pediatr 1990, 776, 714-719)
  • ⁇ -hairpm peptidomimetics of the present invention are compounds of the general formula
  • R 1 is H; lower alkyl; or aryl-lower alkyl
  • R 2 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 6 ') s OR 55 ; -(CH 2 ) m (CHR 61 ) s SR 56 ;
  • R 3 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 6l ) s OR 55 ; -(CH 2 ) m (CHR 6l ) s SR 56 ;
  • R 4 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 6 , ) s OR 55 ; -(CH 2 ) m (CHR 6 ') s SR 56 ; -(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; -(CH 2 ) m (CHR 6l ) s OCONR 33 R 75 ; -(CH 2 ) m (CHR 6, ) s NR 20 CONR 33 R 82 ;
  • R 5 is alkyl; alkenyl; -(CH 2 ) 0 (CHR 61 ) s OR 55 ; -(CH 2 ) 0 (CHR 61 ) S SR 56 ; -(CH 2 ) 0 (CHR 6 ') S NR 33 R 34 ; -(CH2) o (CHR 61 ) s OCONR 33 R 75 ; -(CH 2 ) o (CHR 61 ) NR 20 CONR 33 R 82
  • R 7 is alkyl; alkenyl; -(CH 2 ) q (CHR 6l ) s OR 55 ; -(CH 2 ) q (CHR 61 ) s NR 33 R 34 ; -(CH 2 ) q (CHR 6 ' ) s OCONR 33 R 75 ; -(CH 2 ) q (CHR 6 ' ) S NR 20 CONR 33 R 82 ; -(CH 2 ) r (CHR 6, )
  • R 8 is H; Cl; F; CF ; N0 2 ; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl; -(CH 2 ) o (CHR 6 ') s 0R 55 ; -(CH 2 ) 0 (CHR 61 ) S SR 56 ; -(CH 2 ) 0 (CHR 6 ')NR 33 R 34 ; -(CH 2 ) 0 (CHR 6 ' ) s OCONR 33 R 75 ; -(CH 2 ) 0 (CHR 6 ' ) S NR 20 CONR 33 R 82 ; -(CH 2 ) o (CHR 61 ) s COOR 57 ; -(CH 2 ) 0 (CHR 6 ') S S0 2 R 62 ; or -(CH 2 ) r (CHR 6l ) s C 6 H 4 R 8 ; R 8 is H; Cl; F; CF
  • R 9 is alkyl; alkenyl; -(CH 2 ) 0 (CHR 61 ) s OR 55 ; -(CH 2 ) 0 (CHR 6 ') S SR 56 ; -(CH 2 ) 0 (CHR 61 ) S NR 33 R 34 ; -(CH 2 ) o (CHR 6, ) s OCONR 33 R 75 ; -(CH 2 ) o (CHR 61 ) NR 20 CONR 33 R 82 ; -(CH 2 ) 0 (CHR 6 ' ) s COOR 57 ; -(CH 2 ) 0 (CHR 6 ' ) s CONR 58 R 59 ; -(CH 2 ) 0 (CHR 61 ) S PO
  • R'° is alkyl; alkenyl; -(CH 2 ) 0 (CHR 6l ) s OR 55 ; -(CH 2 ) 0 (CHR 6 ') S SR 56 ; -(CH 2 ) 0 (CHR 6I ) S NR 33 R 34 ; -(CH 2 ) 0 (CHR 61 ) s OCONR 33 R 75 ; -(CH 2 ) 0 (CHR 6 ' ) S NR 20 CONR 33 R 82 ; -(CH 2 ) o (CHR 6 ') s COOR 57 ; -(CH 2 ) o (CHR 6l )-CONR 58 R S9 ; -(CH 2 ) o (CHR 6l ) s PO(OR 60 ) 2 ; -(CH 2 ) 0 (CHR 6 ') S S0 2 R 62 ; or -(CH 2 ) 0 (CHR 6I
  • R 14 is H, alkyl, alkenyl, -(CH 2 ) m (CHR 61 ) s OR 55 , -(CH 2 ) m (CHR 6l ) 5 NR 33 R 34 , -(CH 2 ) m (CHR 6 ') s OCONR 33 R 75 , -(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 , -(CH2) q (C
  • R 16 is alkyl, alkenyl, -(CH 2 ) 0 (CHR 6 ') s OR 55 , -(CH 2 ) 0 (CHR 61 ) S SR 56 , -(CH 2 ) 0 (CHR 6 ') S NR 33 R 34 , -(CH 2 ) 0 (CHR 6 ' ) s OCONR 33 R 75 , -(CH 2 ) 0 (CHR 61 ) S NR
  • R 17 is alkyl, alkenyl, -(CH 2 ) q (CHR 6l ) s OR 55 , -(CH 2 ) q (CHR 6l ) s SR 56 , -(CH 2 ) q (CHR 6 ') s NR 33 R 34 , -(CH 2 ) q (CHR 61 ) s OCONR 33 R 75 , -(CH 2 ) q (CHR 61 ) NR 20 CONR 33 R 82 , -(CH 2 ) q (CHR 6 ' ) s COOR 57 , -(CH 2 ) q (CHR 6 ' ) s CONR 58 R 59 , -(CH 2 ) q (CHR 6 I ) 5 S0 2 R 62 , or -(CH 2 ) 0 (CHR 61 ) S C 6 H 4 R 8 , R 17 is alkyl, alkenyl, -(
  • R 18 is alkyl, alkenyl, -(CH 2 ) p (CHR 61 ) s OR 55 , -(CH 2 ) P (CHR 51 ) 5 SR 56 , -(CH 2 ) P (CHR 6, ) S NR 33 R 34 , -(CH 2 ) p (CHR 6, ) s OCONR 33 R 75 , -(CH 2 ) P (CHR 6, ) S NR 20 CONR 33 R 82 , -(CH 2 )p(CHR 6 l ) 5 COOR 57 , -(CH 2 ) p (CHR 61 ) s CONR 58 R 59 , -(CH 2 ) P (CHR 6 ') S PO(OR 60 ) 2) -(CH 2 ) p (CHR 61 ) s S0 2 R 62 , or -(CH 2 ) 0 (CHR 6 ') S C 6 H 4 R 8 , R 19
  • R 20 is H, alkyl, alkenyl, or aryl-lower alkyl
  • R 2 ' is H, alkyl, alkenyl, -(CH 2 ) 0 (CHR 6l ) s OR 55 , -(CH 2 ) 0 (CHR 6I ) S SR 56 , -(CH 2 ) sanction(CHR 6 ') S NR 33 R 34 , -(CH 2 ) 0 (CHR 6 ' ) 5 OCONR 33 R 75 , -(CH 2 ) 0 (CHR 6 ' ) S NR 20 CONR 33 R 82 , -(CH 2 ) 0 (CHR 61 ) s COOR 57 , -(CH 2 ) 0 (CHR 6 ') s CONR 58 R 59 , -(CH 2 ) o (CHR 6 ') s PO(OR 60 ) 2 , -(CH 2 ) 0 (CHR 61 ) S S0 2 R 62 , or -(CH 2 ) 0 (CHR
  • R 22 is H, alkyl, alkenyl, -(CH 2 ) 0 (CHR 6 ') S OR 55 , -(CH 2 ) 0 (CHR 61 ) S SR 56 , -(CH 2 ) 0 (CHR 6 ') S NR 33 R 34 , -(CH 2 ) 0 (CHR 6 ' ) s OCONR 33 R 7S , -(CH 2 ) 0 (CHR 6 ' ) S NR 20 CONR 33 R 82 , -(CH2)o(CHR 6 ') s COOR 57 , -(CH 2 ) o (CHR 6l ) 3 CONR 58 R 59 , -(CH 2 ) solicit(CHR 6l ) 3 PO(OR 60 ) 2 , -(CH 2 )o(CHR 6l ) s S0 2 R 62 , or -(CH 2 ) 0 (CHR 61 ) S C
  • R 24 is alkyl, alkenyl, -(CH 2 ) 0 (CHR 6l ) s OR 55 , -(CH 2 ) o (CHR 6l ) s SR 56 , -(CH 2 ) 0 (CHR 6I ) S NR 33 R 34 , -(CH 2 ) 0 (CHR 6, ) s OCONR 33 R 75 , -(CH 2 ) o (CHR 61 ) NR 20 CONR 33 R 82 , -(CH 2 ) 0 (CHR 6I ) S COOR 57 , -(CH 2 ) 0 (CHR 6l ) s CONR 58 R 59 , -(CH 2 ) o (CHR 6 ') s PO(
  • R 25 is H, alkyl, alkenyl, -(CH 2 ) m (CHR 6 l ) s OR 55 , -(CH 2 ) m (CHR 6 ') s SR 56 , -(CH 2 ) m (CHR 6l ) s NR 33 R 34 , -(CH 2 ) m (CHR 6l ) s OCONR 33 R 75 , -(CH2) m (CHR 61 ) s NR 20 CONR 33 R 82 , -(CH 2 ) o (CHR ⁇ ') s COOR 57 , -(CH 2 ) o (CHR 61 ) s CONR 58 R 59 , -(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 , -(CH 2 ) o (CHR 61 ) s S0 2 R 62 , or -(CH 2 ) 0 (
  • R 26 is H, alkyl, alkenyl, -(CH 2 ) m (CHR 61 ) s OR 55 , -(CH 2 ) m (CHR 61 ) s SR 56 , -(CH 2 ) m (CHR 61 ) s NR 33 R 34 , -(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ,
  • R 25 and R 26 taken together can form -(CH 2 ) 2 6 -, -(CH 2 ) r O(CH 2 ) r -, -(CH 2 ) r S(CH 2 ) r -, or
  • R 27 is H, alkyl, alkenyl, -(CH 2 ) 0 (CHR 6 ') s OR 55 , -(CH 2 ) 0 (CHR 6I ) S SR 56 , -(CH 2 ) 0 (CHR 6 ') S NR 33 R 34 , -(CH 2 ) 0 (CHR 61 ) s CO0R 57 > -(CH 2 ) o (CHR 6 ') s C0NR 58 R 59 , -(CH 2 ) o (CHR 61 ) s 0C0NR 33 R 75 , -(CH 2 )o(CHR 6l )3NR 20 CONR 33 R 82 , -(CH 2 ) 0 (CHR 6 I ) S PO(OR 60 ) 2 ,
  • R 28 is alkyl, alkenyl, -(CH 2 ) 0 (CHR 61 ) s -OR 55 , -(CH 2 ) 0 (CHR 61 ) S SR 56 , -(CH 2 ) 0 (CHR 6I ) S NR 33 R 34 , -(CH 2 ) 0 (CHR 61 ) s OCONR 33 R 75 , -(CH 2 ) o (CHR 61 ) NR 20 CONR 33 R 82 , -(CH 2 ) 0 (CHR 61 ) S COOR 57 , -(CH 2 ) 0 (CHR ⁇ ') s CONR 58 R 59 , -(CH 2 ) 0 (CHR 61 )
  • R 29 is alkyl, alkenyl, -(CH 2 ) 0 (CHR 6l )-OR 55 , -(CH 2 ) 0 (CHR 6I ) S SR 56 , -(CH 2 ) o (CHR 6l ) s NR 33 R 34 , -(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 , -(CH 2 ) o (CHR 6l ) s NR 20 CONR 33 R 82 , -(CH 2 ) 0 (CHR 6l ) s COOR 57 , -(CH 2 ) o (CHR 6l ) s CONR 58 R 59 , -(CH 2 ) o (CHR 6l ) s PO(OR 60 ) 2 , -(CH 2 ) 0 (CHR 61 ) S S0 2 R 62 , or -(CH 2 ) 0 (CHR 6, )
  • R 31 is H, alkyl, alkenyl, -(CH 2 ) p (CHR ) 5 OR 55 , -(CH 2 ) P (CHR 6 ') S NR 33 R 34 , -(CH 2 )p(CHR 6 ') s OCONR 33 R 75 , -(CH 2 ) p (CHR 6l )-NR 20 CONR 33 R 82 , -(CH 2 ) o (CHR 6 ') s COOR 57 ; -(CH 2 ) o (CHR 6l )-CONR 58 R 59 ; -(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; -(CH 2 ) 0 (CHR 61 )-S0 2 R 62 ; or -(CH 2 ) 0 (CHR 61 ) S C 6 H 4 R 8 ; R 32 is H; lower alkyl; or aryl-lower al
  • R 33 is H; alkyl, alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 6 ') s NR 34 R 63 ; -(CH 2 ) m (CHR 6 ') s OCONR 75 R 82 ; -(CH 2 ) m (CHR 6, ) s NR 20 CONR 78 R 82 ;
  • R 34 is H; lower alkyl; aryl, or aryl-lower alkyl;
  • R 33 and R 34 taken together can form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -;
  • R 35 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 6 ') s 0R 55 ; -(CH 2 ) m (CHR 6l ) 5 NR 33 R 34 ; -(CH 2 ) worship,(CHR 6 ' ) s 0C0NR 33 R 75 ; -(CH 2 ) m (CHR 6 ' ) S NR 20 CONR 33 R 82 ; -(CH2)p(CHR 6 ') s COOR 57 ; -(CH2) p (CHR 61 ) s CONR 58 R 59 ; -(CH 2 ) p (CHR 6 ') s PO(OR 60 )2; -(CH 2 ) P (CHR 61 ) s S0 2 R 62 ; or -(CH 2 ) P (CHR 6, ) S H.R 8 ; R 36 is H, alkyl; alkenyl;
  • R 39 is H; alkyl; alkenyl; or aryl-lower alkyl; R is H; alkyl; alkenyl; or aryl-lower alkyl;
  • R 4 ' is H; F; Br; Cl; N0 2 ; CF 3 ; alkyl; alkenyl; -(CH 2 ) P (CHR 61 ) S 0R 55 ; -(CH 2 ) P (CHR 6 ') S NR 33 R 34 ; -(CH 2 ) p (CHR 6 l ) s OCONR 33 R 75 ; -(CH 2 ) P (CHR 61 ) S NR 20 CONR 33 R 82 ;
  • R 42 is H; F; Br; Cl; N0 2 ; CF 3 ; alkyl; alkenyl; -(CH 2 ) p (CHR 6, ) s OR 55 ; -(CH 2 ) P (CHR 6 ') S NR 33 R 34 ; -(CH 2 ) P (CHR 6 ' ) s OCONR 33 R 75 ; -(CH 2 ) P (CHR 6 ' ) S NR 20 CONR 33 R
  • R 43 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 6l ) s OR 55 ; -(CH 2 ), n (CHR 6l ) s NR 33 R 34 ; -(CH 2 ) m (CHR 6 ' ) s OCONR 33 R 75 ; -(CH 2 ) m (CHR 61 ) S NR 20 CONR 33 R 82 ; -(CH2)o(CHR 6l ) s COOR 57 ; -(CH2) o (CHR 6l ) s CONR 58 R 59 ; -(CH 2 ) o (CHR 6l ) s PO(OR 60 )2; -(CH 2 ) 0 (CHR 6 l
  • R 46 is H; alkyl; alkenyl; or -(CH 2 ) 0 (CHR 6 ') P C 6 H 4 R 8 ;
  • R 47 is H; alkyl; alkenyl; or -(CH 2 ) 0 (CHR 6l ) s OR 55 ;
  • R 4 is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;
  • R 49 is H; alkyl; alkenyl; -(CHR 6l ) s COOR 57 ; (CHR 5 ') s CONR 58 R 59 ; (CHR 6 ') S PO(OR 60 ) 2 ; -(CHR 6l ) s SOR 62 ; or -(CHR 61 ) S C 6 H 4 R 8 ;
  • R 51 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 6 ') s OR 5S ; -(CH 2 ) m (CHR 6l ) s SR 56 ; -(CH 2 ) m (CHR 6 ') s NR 33 R 34 ; -(CH 2 ) m (CHR 6l ) s OCONR 33 R 75 ; -(CH 2 ) rn (CHR 6 ')-NR 20 CONR 3 R 82 ; -(CH 2 ) 0 (CHR 6l ) s COOR 57 ;
  • R 52 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 6, ) s SR 56 ; -(CH 2 ) m (CHR 6 ' ) S NR 33 R 34 ; -(CH 2 ) m (CHR 6 ' ) S OCONR 33 R 75 ; -(CH 2 ) m (CHR 6 ') s NR 20 CONR 33 R 82 ; -(CH 2 ) 0 (CHR
  • R 53 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 6l ) s OR 55 ; -(CH 2 ) m (CHR 6l ) s SR 56 ; -(CH 2 ) m (CHR 6l ) s NR 33 R 34 ; - (CH 2 ) accent,(CHR 6 ') s OCONR 33 R 75 ; -(CH 2 ) m (CHR 6l ) s NR 20 CONR 33 R 82 ; -(CH 2 ) o (CHR
  • R 54 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 6 ') s OR 55 ; -(CH 2 )- n (CHR 6 ') s NR 33 R 34 ; -(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; -(CH 2 ) n ,(CHR 61 )-NR 0 CONR 33 R 82 ; -(CH 2 ) o (CHR 6 l )COOR 57 ; -(CH 2 ) 0 (CHR 6,
  • R 55 is H; lower alkyl; lower alkenyl; aryl-lower alkyl; -(CH 2 ) m (CHR 6 ') s OR 57 ; -(CH 2 ) m (CHR 6 ') s NR 34 R 63 ; -(CH 2 ) m (CHR 6l )-OCONR 75 R 82 ; -(CH 2 ) m (CHR 6l ) s NR 20 CONR 78 R 82 , -(CH 2 ) felicit(CHR 6 ') s -COR 64 , -(CH 2 ) 0 (CHR 61 )COOR 57 , or -(CH 2 ) 0 (CHR 6 ') S CONR 58 R 59 , R 56 is H, lower alkyl, lower alkenyl, aryl-lower alkyl, -(CH 2 ) m (CHR 61 ) s OR 57 ,
  • R 57 is H, lower alkyl, lower alkenyl, aryl lower alkyl, or heteroaryl lower alkyl
  • R 58 is H, lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, or heteroaryl-lower alkyl
  • R is H, lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, or heteroaryl-lower alkyl
  • R 58 and R 59 taken together can form -(CH 2 ) 2 6 -, -(CH 2 ) 2 0(CH 2 ) 2 -, -(CH 2 ) 2 S(CH 2 ) 2 -, or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -
  • R 60 is H, lower alkyl, lower alkenyl, aryl, or
  • R 61 is alkyl, alkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, -(CH 2 ) lake,OR 55 , -(CH 2 ) n ,NR 33 R 34 , -(CH 2 ) m OCONR 75 R 82 , -(CH 2 ) m NR 20 CONR 78 R 82 , -(CH 2 ) 0 COOR 37 , -(CH 2 ) 0 NR 58 R 59 , or -(CH 2 ) o PO(COR 60 ) 2 ,
  • R * is lowei alkyl, lower alkenyl, aryl, heteroaryl, or aryl-lower alkyl
  • R 63 is H, lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl,
  • -COR 64 , -COOR 57 , -CONR 58 R 59 , -SO,R 62 , or -PO(OR 60 ) 2 , R 34 and R 03 taken together can form -(CH 2 ) 2 6 -, -(CH 2 ) 2 0(CH 2 ) 2 -, -(CH 2 ) 2 S(CH 2 )2-, or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -,
  • R 64 is H, lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, -(CH 2 ) p (CHR ⁇ ") s OR 65 , -(CH 2 ) P (CHR 6 I ) S SR 66 , or -(CH 2 ) P (CHR 6I )-NR 34 R 63 , -(CH 2 ) P (CHR 6l ) s OCONR 75 R 82 , -(CH 2 )p(CHR 6l ) s NR 20 CONR 78 R 82 , R 65 is H, lower alkyl, lower alkenyl, aryl, aryl-lower alkyl, heteroaryl-lower alkyl, -COR 57 , -COOR 57 , or -CONR 58 R 59 ,
  • R 66 is H, lower alkyl, lower alkenyl, aryl, aryl-lower alkyl, heteroaryl-lower alkyl, or
  • m is 2-4, o is 0-4, p is 1-4, q is 0-2, r is 1 or 2, s is 0 or 1 ,
  • Z is a chain of 12 ⁇ -amino acid residues, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, whereby these amino acid residues are, depending on their position in the chain, Gly or Pro, or of formula -A-CO-, or of formula -B-CO-, or of one of the types
  • R 71 is H, lower alkyl, lower alkenyl, -(CH 2 ) p (CHR 6, ) s OR 75 , -(CH 2 ) p (CHR 6, ) s SR 75 ,
  • R 73 is -(CH 2 ) P (CHR 61 ) S NR 33 R 34 , -(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 , -(CH 2 ) P (CHR 6 ') S NR 20 CONR 33 R 82 , -(CH 2 ) 0 (CHR 6l ) s COOR 75 , -(CH 2 ) P C0NR 58 R 59 , -(CH 2 ) p PO(OR 62 ) 2 , -(CH 2 ) p S0 2 R 62 , or -(CH 2 ) o -C 6 R 67 R 68 R 69 R 70 R 76 , R 72 is H, lower alkyl, lower alkenyl, -(CH 2 ) p (CHR 6 ') s OR 85 , or -(CH 2 ) P (CHR 6 ') S SR 85 , R 73 is -(
  • R 75 is lower alkyl, lower alkenyl, or aryl-lower alkyl, R 33 and R 75 taken together can form -(CH 2 ) 2 6 -, -(CH 2 ) 2 0(CH 2 ) 2 -, -(CH 2 ) 2 S(CH 2 ) 2 -, or
  • -(CH 2 ) 2 NR 57 (CH 2 ) 2 -, R 75 and R 82 taken together can form -(CH 2 ) 2 6 -, -(CH 2 ) 2 0(CH 2 ) 2 -, -(CH 2 ) 2 S(CH 2 ) 2 -, or
  • R 76 is H, lower alkyl, lower alkenyl, aryl-lower alkyl, -(CH 2 ) 0 0R 72 , -(CH 2 ) 0 SR 72 , -(CH 2 ) 0 NR 33 R 34 , -(CH 2 ) 0 0C0NR 33 R 75 , -(CH 2 ) o NR 20 CONR 33 R 82 , -(CH 2 ) 0 COOR 75 ; -(CH 2 ) 0 CONR 58 R 59 ; -(CH 2 ) o PO(OR 60 ) 2 ; -(CH 2 ) p S0 2 R 62 ; or -(CH 2 ) 0 COR 64 ;
  • R" is -C 6 R 6/ R 68 R 69 R' U R 76 ; or a heteroaryl group of one of the formulae
  • R 78 is H; lower alkyl; aryl; or aryl-lower alkyl;
  • R 78 and R 82 taken together can form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -;
  • R is H; lower alkyl; aryl; or aryl-lower alkyl; or
  • R 78 and R 79 taken together, can be -(CH 2 ) 2 . 7 -; -(CH 2 ) 2 0(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -;
  • R 80 is H; or lower alkyl;
  • R 81 is H, lower alkyl, or aryl-lower alkyl,
  • R 82 is H, lower alkyl, aryl, heteroaryl, or aryl-lower alkyl,
  • R 33 and R 82 taken together can form -(CH 2 ) 2 . 6 -, -(CH 2 ) 2 0(CH 2 ) 2 -, -(CH 2 ) 2 S(CH 2 ) 2 -, or -(CH 2 ) 2 NR S (CH 2 ) 2 -, R 83 ⁇ s H, lower alkyl, aryl, or -NR 78 R 79 ,
  • R 84 is -(CH 2 ) m (CHR 6l ) s OH, -(CH 2 ) p CONR 78 R 79 , -(CH 2 ) P NR 80 CONR 78 R 79 , -(CH 2 ) p C 6 H 4 CONR 78 R 79 , or -
  • P10 of type F, or of type D or of type C, or the residue is Pro, Pl l of type E or of type D or of type C or of type F, and PI 2 of type C or of type D or of type E or of type F, or the residue is Pro, or P4 and P9 and/or P2 and PI 1, taken together, can form a group of type H, and at P6 and P7 also D-isomers being possible, with the further proviso that the amino acid residue in P4 is of type C, and/or the amino acid residue in P5 is of type F, and/or the ammo acid residue m P7 is of type C, and/or - the amino acid residue in P8 is of type F, and or the amino acid residue in P9 is of type C, and/or the amino acid residue in PI 0 is of type F, and/or the amino acid residue in PI 1 is of type C or of type F, and pharmaceutically acceptable salts thereof
  • these ⁇ -hairpin peptidomimetics can be prepared by a process which comprises (a) coupling an appropriately functionahzed solid support with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 5, 6 or 7, any functional group which may be present in said N-protected ammo acid derivative being likewise appropriately protected,
  • X is an N-protectmg group or, if
  • step (e) is to be group (al) or (a2), above, alternatively (fa) coupling the product obtained in step (e) with an appropriately N-protected derivative of an amino acid of the general formula
  • the peptidomimetics of the present invention can be prepared by
  • X is as defined above and X is an N-protectmg group or, if s to be group (al) or (a2), above, alternatively
  • the peptidomimetics of the present invention can also be enantiomers of the compounds of formula I These enantiomers can be prepared by a modification of the above processes m which enantiomers of all chiral starting materials are used
  • alkyl designates saturated, straight-chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms
  • alkenyl designates straight chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds
  • lower designates radicals and compounds having up to 6 carbon atoms
  • the term “lower alkyl” designates saturated, straight-chain or branched hydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert -butyl and the like
  • aryl designates aromatic carbocyc c hydrocarbon radicals containing one or two six-membered rings
  • the structural element -A-CO- designates ammo acid building blocks which in combination with the structural element -B-CO- form templates (al) and (a2) Templates (a) through (p) constitute building blocks which have an N-termmus and a C-terminus oriented in space in such a way that the distance between those two groups may he between 40-5 5A
  • a peptide chain Z is linked to the C-termmus and the N-terminus of the templates (a) through (p) via the corresponding N- and C-termim so that the template and the chain form a cyclic structure such as that depicted in formula I.
  • the ⁇ -hairpin conformation is highly relevant for the antibiotic activity of the ⁇ -hairpin mimetics of the present invention
  • the ⁇ -hairpin stabilizing conformational properties of the templates (a) through (p) play a key role not only for the selective antimicrobial activity but also for the synthesis process defined hereinabove, as incorporation of the templates at the beginning of the linear protected peptide precursors enhance significantly cyclization yields
  • Building blocks A1-A69 belong to a class of amino acids wherein the N-terminus is a secondary amine forming part of a ring Among the genetically encoded amino acids only proline falls into this class
  • the configuration of building block Al through A69 is (D), and they are combined with a building block -B-CO- of (L)-configurat ⁇ on
  • Preferred combinations for templates (al) are- D Al-CO- L B-CO- to D A69-CO- L B-CO-
  • D Pro- L Pro constitutes the prototype of templates (al)
  • templates (a2) are -' Al-CO- D B-CO- to L A69-CO- D B-CO-
  • L Pro- D Pro constitutes a less preferred prototype of template (a2)
  • building blocks -Al-CO- to -A69-CO- in which A has (D)-conf ⁇ gurat ⁇ on are ca ⁇ ying a group R 1 at the ⁇ -position to the N-te ⁇ mnus
  • the prefe ⁇ ed values for R 1 are H and lower alkyl with the most preferred values for R 1 being H and methyl
  • A1-A69 are shown in (D)-conf ⁇ guratwn which, for R' being H and methyl, corresponds to the (R)-configurat ⁇ on
  • this configuration may also have to be expressed as (S)
  • R 2 to R 17 can carry an additional substituent designated as R 2 to R 17
  • This additional substituent can be H, and if it is other than H, it is preferably a small to medium-sized aliphatic or aromatic group
  • R 2 to R 17 are R : H, lower alkyl, lower alkenyl, (CH 2 ) m OR 55 (where R 55 lower alkyl, or lower alkenyl), (CH 2 ) nl SR 56 (where R 56 lower alkyl, or lower alkenyl), (CH 2 ), ruleNR 33 R 34 (where R 33 lower alkyl, or lower alkenyl, R 34 H, or lower alkyl, R 33 and R 34 taken together form
  • R 3 H lower alkyl, lower alkenyl, -(CH 2 ) m OR 55 (where R 55 lower alkyl, or lower alkenyl), - (CH 2 ) m SR 56 (where R 56 lower alkyl, or lower alkenyl), -(CH 2 ) m NR 33 R 34 (where R 33 lower alkyl, or lower alkenyl, R 34 H, or lower alkyl, or R 33 and R 34 taken together form -(CH 2 ) 2 6 -, -(CH 2 ) 2 0(CH 2 ) 2 - , -(CH 2 ) 2 S(CH 2 ) 2 -, or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -, where R 57 H, or lower alkyl), -(CH 2 ) m OCONR 33 R 75 (where R 33 H, or lower alkyl, or lower alkenyl, R 75 lower alkyl, or R 33 and R 75 taken together fon
  • NR 33 R 34 where R 33 lower alkyl, or lower alkenyl, R 34 H, or lower alkyl, or R 33 and R 34 taken together form -(CH 2 ) 2 ⁇ ,-, -(CH 2 ).0(CH 2 ) 2 - , -(CH 2 ) 2 S(CH 2 ) 2 -, or -(CH 2 ) 2 NR 57 (CH 2 ),-, where R 57 H, or lower alkyl), -(CH 2 ) m OCONR 33 R 75 (where R 33 H, or lower alkyl, or lower alkenyl, R 75 lower alkyl, or R 33 and R 75 taken together form - (CH 2
  • R 33 H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 59 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -;
  • R 60 lower alkyl; or lower alkenyl); -(CH 2 ) 0 S0 2 R 62 (where R 62 : lower alkyl; or lower alkenyl); or - (CH 2 ) q C6H-
  • R 7 lower alkyl; lower alkenyl; -(CH 2 ) q OR 55 (where R 55 : lower alkyl; or lower alkenyl); -
  • R s H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; -(CH 2 ) 0 OR 55 (where R 55 : lower alkyl; or lower alkenyl); (CH 2 ) 0 SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) 0 NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 82 (where R 20 : H; or lower lower alkyl; R 33 : H; or lower alkyl; or lower alkenyl; R 82 : H; or lower alkyl; or R 33 and R 82 taken together form: -(CH 2 ) 2 .
  • R 9 lower alkyl; lower alkenyl; -(CH 2 ) 0 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) 0 SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) 0 NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R'° lower alkyl; lower alkenyl; -(CH 2 ) 0 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) 0 SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) 0 NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form:
  • R" H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) m SR 56 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 - 6 -; -(CH 2 ) 2 0(CH 2 ) 2 - ; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR S7 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) m 0C0NR 33 R 75
  • R 33 H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: - (CH, ; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 12 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) m SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R u lower alkyl; lower alkenyl; -(CH 2 ) q 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) q SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) q NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 14 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) m SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 16 lower alkyl; lower alkenyl; -(CH 2 ) 0 OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) 0 SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) 0 NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form:
  • R 17 lower alkyl, lower alkenyl, -(CH 2 ) q OR 55 (where R 55 lower alkyl, or lower alkenyl), - (CH 2 ) q SR 56 (where R 56 lower alkyl, or lower alkenyl), -(CH 2 ) q NR 33 R 34 (where R 33 lower alkyl, or lower alkenyl, R 34 H, or lower alkyl, or R 33 and R 34 taken together form
  • building blocks Al to A69 the following are preferred A5 with R 2 being H, A8, A22, A25, A38 with R 2 being H, A42, A47, and A50 Most preferred are building blocks of type A8'
  • R 20 is H or lower alkyl
  • R 64 is alkyl, alkenyl, aryl, aryl-lower alkyl, or heteroaryl-lower alkyl, especially those wherein R 64 is n-hexyl (A8'-l), n-heptyl (A8'-2), 4-(phenyl)benzyl (A8'-3), diphenylmethyl (A8'-4), 3-ammo-propyl (A8'-5), 5-am ⁇ no-pentyl (A8'-6), methyl (A8'-7), ethyl (A8'-8), isopropyl (A8'-9), isobutyl (A8'-10), n-propyl (A8'-ll), cyclohexyl (A8*-12), cyclohexylmethyl (A8'-13), n-butyl (A8'-14), phenyl (A8'-15), benzyl (A8'-16
  • Building block A70 belongs to the class of open-chained ⁇ -substituted ⁇ -amino acids, building blocks A71 and A72 to the corresponding ⁇ -amino acid analogues and building blocks A73-A104 to the cyclic analogues of A70
  • Such amino acid derivatives have been shown to constrain small peptides in well defined reverse turn or U-shaped conformations (C M Venkatachalam, Biopolymers, 1968, 6, 1425-1434, W Kabsch, C Sander, Biopolymers 1983, 22, 2577)
  • Such building blocks or templates are ideally suited for the stabilization of ⁇ -hairpin conformations in peptide loops (D Obrecht, M Altorfer, J A Robinson, "Novel Peptide Mimetic Building Blocks and Strategies for Efficient Lead Finding", Adv Med Chem 1999, Vol 4, 1-68, P Balaram, "Non-standard amino acids in peptide design and protein engineering", Curr Opin Struct Biol 1992, 2, 845-851
  • templates (al) can also consist of -A70-CO- to A104- CO- where building block A70 to A104 is of either (D)- or (L)-configurat ⁇ on, in combination with a building block -B-CO- of (L)- configuration
  • Preferred values for R 20 in A70 to A104 are ⁇ or lower alkyl with methyl being most preferred Preferred values for R 18 , R 19 and R 21 -R 29 in building blocks A70 to A104 are the following R' 8 lower alkyl - R' 9 lower alkyl, lower alkenyl, -(C ⁇ 2 ) p OR 55 (where R 55 lower alkyl, or lower alkenyl), -
  • R" lower alkyl; lower alkenyl; -(CH 2 ) 0 OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) 0 SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) 0 NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form:
  • R 60 lower alkyl; or lower alkenyl
  • -(CH 2 ) 0 S0 2 R 62 (where R 62 : lower alkyl; or lower alkenyl); or -
  • R 8 H; F; Cl; CF; lower alkyl; lower alkenyl; or lower alkoxy.
  • R 23 H; lower alkyl; lower alkenyl; -(CH 2 ) 0 OR 55 (where R 55 : lower alkyl; or lower alkenyl); -
  • R 33 H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 8 H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy
  • R 24 lower alkyl; lower alkenyl; -(CH 2 ) 0 0R 55 (where R 55 : lower alkyl; or lower alkenyl); -
  • R 33 H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 8 H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy
  • R 25 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 _ 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) m 0C0NR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2 - «
  • R 26 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 )2S(CH 2 ) 2 -; or
  • R 25 and R 26 taken together can be -(CH 2 ) 2 -6-; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl).
  • R 27 H; lower alkyl; lower alkenyl; -(CH 2 ) 0 OR 55 (where R 55 : lower alkyl; or lower alkenyl); -
  • R 2S lower alkyl; lower alkenyl; -(CH 2 ) 0 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) 0 SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) 0 NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form:
  • R 31 H; lower alkyl; lower alkenyl; -(CH 2 ) P 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 33 lower alkyl; lower alkenyl; -(CH 2 ) m 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) m NR 34 R 63 (where R 34 : lower alkyl; or lower alkenyl; R 63 : H; or lower alkyl; or R 34 and R 63 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 34 H; or lower alkyl.
  • R 35 H; lower alkyl; lower alkenyl; -(CH 2 ) m 0R 55 (where R 55 : lower alkyl; or lower alkenyl); -
  • (CH 2 ) m NR 33 R 34 (Where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 - ; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) m OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2 - 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 )
  • R 36 lower alkyl; lower alkenyl; or aryl-lower alkyl.
  • R 37 H; lower alkyl; lower alkenyl; -(CH 2 ) p OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) p NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 3S H; lower alkyl; lower alkenyl; -(CH 2 ) P 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 - 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 39 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 5S (where R S5 : lower alkyl; or lower alkenyl); - (CH 2 ) n .N(R 20 )COR 64 (where: R 20 : H; or lower alkyl; R 64 : lower alkyl; or lower alkenyl); - (CH 2 ) 0 COOR 57 (where R 57 : lower alkyl; or lower alkenyl); -(CH 2 ) 0 CONR 58 R 59 (where R 58 : lower alkyl; or lower alkenyl; and R 59 : H; lower alkyl; or R 58 and R 59 taken together form: -(CH 2 ) .
  • R 40 lower alkyl; lower alkenyl; or aryl-lower alkyl.
  • R 4 ' H; lower alkyl; lower alkenyl; -(CH 2 ) P 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 42 H; lower alkyl; lower alkenyl; -(CH 2 ) P 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 _ 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 - ; or
  • R 43 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) m SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form:
  • R 44 lower alkyl; lower alkenyl; -(CH 2 ) p OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) P SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form:
  • R 45 H; lower alkyl; lower alkenyl; -(CH 2 ) 0 OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) 0 SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) 0 NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form:
  • R 46 H; lower alkyl; lower alkenyl; -(CH 2 ) s OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) S SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) S NR 3 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form:
  • R 47 H; or OR 55 (where R 55 : lower alkyl; or lower alkenyl).
  • R" H or lower alkyl.
  • R 57 H; or lower alkyl
  • R 8 H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy.
  • R 50 H; methyl.
  • R 5 ' H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 52 H; lower alkyl; lower alkenyl; -(CH ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 0(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 53 H; lower alkyl; lower alkenyl; -(CH 2 ) m 0R 55 (where R 55 : lower alkyl; or lower alkenyl); - (CH 2 ), ruleNR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • building blocks A70 to A104 the following are preferred: A74 with R 22 being H, A75, A76, A77 with R 22 being H, A78 and A79.
  • the building block -B-CO- within template (al) and (a2) designates an L-amino acid residue.
  • Preferred values for B are: -NR 20 CH(R 71 )- and enantiomers of groups A5 with R 2 being H, A8, A22, A25, A38 with R 2 being H, A42, A47, and A50.
  • Most preferred are Ala L-Alanine
  • the most preferred values for B also include groups of type A8" of (L)-conf ⁇ gurat ⁇ on
  • R 20 is H or lower alkyl and R 64 is alkyl, alkenyl, aryl, aryl-lower alkyl, or heteroaryl-lower alkyl, especially those wherein R 64 is n-hexyl (A8"-21), n-heptyl (A8"-22), 4-(phenyl)benzyl (A8"- 23), diphenylmethyl (A8"-24), 3-am ⁇ no-propyl (A8"-25), 5-am ⁇ no-pentyl (A8"-26), methyl (A8 M - 27), ethyl (A8"-28), isopropyl (A8"-29), isobutyl (A8"-30), n-propyl (A8"-31), cyclohexyl (A8"- 32), cyclohexylmethyl (A8"-33), n-butyl (A8"-34), phenyl (A8"-35),
  • the peptidic chain Z of the ⁇ -hai in mimetics described herein is generally defined in terms of amino acid residues belonging to one of the following groups
  • amino acid residues m chain Z can also be of formula -A-CO- or of formula -B-CO- wherein A and B are as defined above
  • Gly can also be an amino acid residue in chain Z
  • Pro can be an ammo acid residue in chain Z, too, with the exception of positions where interstrand linkages (H) are possible
  • Group C comprises amino acid residues with small to medium-sized hydrophobic side chain groups according to the general definition for substituent R 72
  • a hydrophobic residue refers to an amino acid side chain that is uncharged at physiological pH and that is repelled by aqueous solution
  • these side chains generally do not contain hydrogen bond donor groups, such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas
  • they may contain hydrogen bond acceptor groups such as ethers, thioethers, esters, tertiary amides, alkyl- or aryl phosphonates and phosphates or tertiary amines
  • Genetically encoded small-to-medium-sized amino acids include alanine, isoleucine, leucine, methionine and valine
  • Group D comprises ammo acid residues with aromatic and heteroaromatic side chain groups according to the general definition for substituent R 73
  • An aromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated ⁇ - electron system (aromatic group)
  • they may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, ternary amides, alkyl- or aryl phosphonates -and phosphates or tertiary amines Genetically encoded aromatic amino acids include phenylalanine and tyrosine
  • a heteroaromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated ⁇ -system incorporating at least one heteroatom such as (but not limited to) O, S and N according to the general definition for substituent R 77
  • residues may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, ternary amides, alkyl- or aryl phosphonates - and phosphates or tertiary amines Genetically encoded heteroaromatic amino acids include tryptophan and histidine
  • Group E comprises amino acids containing side chains with polar-cationic, acylamino- and urea- derived residues according to the general definition for substituen R
  • Polar-cationic refers to a basic side chain which is protonated at physiological pH
  • Genetically encoded polar-cationic ammo acids include arginine, lysine and histidine Citrulhne is an example for an urea derived amino acid residue
  • Group F comprises ammo acids containing side chains with polar-non-charged residues according to the general definition for substituent R 84
  • a polar-non-charged residue refers to a hydrophilic side chain that is uncharged at physiological pH, but that is not repelled by aqueous solutions
  • Such side chains typically contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas These groups can form hydrogen bond networks with water molecules In addition they may also contain hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tet ⁇ ary amides, alkyl- or aryl phosphonates -and phosphates or tertiary amines Genetically encoded polar-non-charged amino acids include asparagme, cysteine, glutamine, serine and threon
  • Group H comprises side chains of preferably (L)-am ⁇ no acids at opposite positions of the ⁇ -strand region that can form an interstrand linkage
  • the most widely known linkage is the disulfide bridge formed by cystemes and homo-cysteines positioned at opposite positions of the ⁇ -strand
  • Various methods are known to form disulfide linkages including those described by J P Tam et al Synthesis 1979, 955-957, Stewart et al , Solid Phase Peptide Synthesis, 2d Ed , Pierce Chemical Company, III , 1984, Ahmed et al J Biol Chem 1975, 250, 8477-8482 , and Pennington et al , Peptides, pages 164- 166, Giralt and Andreu, Eds , ESCOM Leiden, The Netherlands, 1990
  • disulfide linkages can be prepared using acetamidomethyl ( Acm)- protective groups for cysteine
  • a well established interstrand linkage consists in linking ornithines and
  • residues for group C are Ala L-Alanine
  • Particularly prefened residues for group E are Arg L-Argimne
  • the peptidic chain Z within the ⁇ -hairpin mimetics of the invention comprises 12 amino acid residues
  • Each of the positions PI to PI 2 will preferably contain an amino acid residue belonging to one of the above types C to F, or of fomiula -A-CO- or of formula -B-CO- as follows
  • amino acid residues in positions PI to P12 are - PI Arg
  • PI 2 Arg with the proviso that the amino acid residue in position P4 is Val, and/or the amino acid residue in position P9 is Leu or Val, and/or the amino acid residue in position P10 is Thr or Gin, and/or the amino acid residue in position PI 1 is Val or Leu or Gin
  • Particularly prefened ⁇ -peptidomimetics of the invention include those described in Examples 1 , to 8
  • the processes of the invention can advantageously be carried out as parallel array syntheses to yield libraries of template-fixed ⁇ -hairpin peptidomimetics of the above general formula I
  • Such parallel syntheses allow one to obtain anays of numerous (normally 24 to 192, typically 96) compounds of general formula I in high yields and defined purities, minimizing the formation of dimeric and polymeric by-products
  • the proper choice of the functionalized solid-support (I e solid support plus linker molecule), templates and site of cyclization play thereby key roles
  • the functionalized solid support is conveniently derived from polystyrene crosshnked with, preferably 1-5%, divinylbenzene, polystyrene coated with polyethyleneglycol spacers (Tentagel R ), and polyacrylamide resins (see also Obrecht, D , Villalgordo, J -M, "Solid- Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries", Tetrahedron Organic Chemistry Series, Vol 17, Pergamon, Elsevier Science, 1998)
  • the solid support is functionalized by means of a linker, l e a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures
  • the linker must be designed to eventually release the carboxyl group under mild acidic conditions which do not affect protecting groups present on any functional group in the side-chains of the various amino acids
  • Linkers which are suitable for the purposes of the present invention form acid-labile esters with the carboxyl group of the amino acids, usually acid-labile benzyl, benzhydryl and t ⁇ tyl esters, examples of linker structures of this kind include 2-methoxy-4-hydroxymethylphenoxy (Sas ⁇ n R linker), 4-(2,4-d ⁇ methoxyphenyl- hydroxymethyl)-phenoxy (Rink linker), 4-(4-hydroxymethyl-3-methoxyphenoxy)buty ⁇ c acid (HMPB linker),
  • the support is derived from polystyrene crosshnked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 2-chlorotntyl linker
  • the processes of the invention can be advantageously earned out as described herein below but it will be immediately apparent to those skilled in the art how these procedures will have to be modified in case it is desired to synthesize one single compound of the above formula I
  • reaction vessels normally 24 to 192, typically 96
  • 25 to 1000 mg preferably 100 mg
  • of the appropriate functionalized solid support preferably 1 to 3% cross linked polystyrene or tentagel resin
  • the solvent to be used must be capable of swelling the resin and includes, but is not limited to, dichloromethane (DCM), dimethylformamide (DMF), N-methylpyrrohdone (NMP), dioxane, toluene, tetrahydrofuran (THF), ethanol (EtOH), tnfluoroethanol (TFE), isopropylalcohol and the like
  • Solvent mixtures containing as at least one component a polar solvent e g 20% TFE/DCM, 35% THF/NMP
  • Suitable protecting groups for amino acids and, respectively, for their residues are, for example,
  • guanidino group (as is present e. g. in the side-chain of arginine)
  • the 9-fluorenylmethoxycarbonyl- (Fmoc)-protected amino acid de ⁇ vatives are preferably used as the building blocks for the construction of the template-fixed ⁇ -hairpin loop mimetics of formula I
  • I e cleaving off of the Fmoc group 20% pipe ⁇ dine in DMF or 2% DBU/2% pipe ⁇ dine in DMF can be used
  • the quantity of the reactant, l e of the ammo acid derivative is usually 1 to 20 equivalents based on the milhequivalents per gram (meq/g) loading of the functionalized solid support (typically 0 1 to 2 85 meq/g for polystyrene resins) originally weighed into the reaction tube Additional equivalents of reactants can be used if required to dnve the reaction to completion in a reasonable time
  • the reaction tubes, in combination with the holder block and the manifold, are reinserted into the reservoir block and the apparatus is fastened together Gas flow through the manifold is initiated to provide a controlled environment, for example, nitrogen, argon, air and the like The gas flow may also be heated or chilled prior to flow through the manifold Heating or cooling of the reaction wells is achieved by heating the reaction block or cooling externally with lsopropanol/dry ice and the like to bring about the desired synthetic reactions Agitation is achieved by shaking or magnetic stirnng (within the reaction tube)
  • reaction wells are filled with solvent (preferably 5 ml), the reaction tubes, in combination with the holder block and manifold, are immersed and agitated for 5 to 300 minutes, preferably 15 minutes, and drained by gravity followed by gas pressure applied through the manifold inlet (while closing the outlet) to expel the solvent,
  • solvent preferably 5 ml
  • Both of the above washing procedures are repeated up to about 50 times (preferably about 10 times), monitoring the efficiency of reagent, solvent, and byproduct removal by methods such as TLC, GC, or inspection of the washings
  • Detachment of the fully protected linear peptide from the solid support is achieved by immersion of the reaction tubes, m combination with the holder block and manifold, in reaction wells containing a solution of the cleavage reagent (preferably 3 to 5 ml) Gas flow, temperature control, agitation, and reaction monitoring are implemented as described above and as desired to effect the detachment reaction
  • the reaction tubes, in combination with the holder block and manifold are disassembled from the reservoir block and raised above the solution level but below the upper hp of the reaction wells, and gas pressure is applied through the manifold inlet (while closing the outlet) to efficiently expel the final product solution into the reservoir wells
  • the resin remaining in the reaction tubes is then washed 2 to 5 times as above with 3 to 5 ml of an appropriate solvent to extract (wash out) as much of the detached product as possible
  • the product solutions thus obtained are combined, taking care to avoid cross-mixing
  • the individual solutions/extracts are then manipulated as needed to isolate the final compounds
  • Interstrand linkages and their formation have been discussed above, in connection with the explanations made regarding groups of the type H which can, for example, be disulfide bndges formed by cysteines and homocysteines at opposite positions of the ⁇ -strand, or glutamic and aspartic acid residues linking ornithines and, respectively, lysines located at opposite ⁇ -strand positions by amide bond formation
  • groups of the type H which can, for example, be disulfide bndges formed by cysteines and homocysteines at opposite positions of the ⁇ -strand, or glutamic and aspartic acid residues linking ornithines and, respectively, lysines located at opposite ⁇ -strand positions by amide bond formation
  • the formation of such interstrand linkages can be effected by methods well known in the art
  • the fully protected peptide derivative of type I is treated with 95% TFA, 2 5% H 2 0, 2 5% TIS or another combination of scavengers for effecting the cleavage of protecting groups
  • the cleavage reaction time is commonly 30 minutes to 12 hours, preferably about 2 hours
  • most of the TFA is evaporated and the product is precipitated with ether/hexane (1 1) or other solvents which are suitable therefor
  • the cyclic peptide derivative obtained as end- product can be isolated Depending on its pu ⁇ ty, this peptide derivative can be used directly for biological assays, or it has to be further purified, for example by preparative HPLC
  • A14 Amino acids of type A14 can be made according to Scheme 1 Scheme 1
  • A30 and A31 can be prepared according to Schemes 4 and 5
  • i HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v. lithium hexamethyldisilazide, THF, -78°, 43; vi: Pd/C, H 2 , EtOH; then DBU,
  • i HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v: lithium hexamethyldisilazide, THF, -78°, 47; vi: Pd/C, H 2 , EtOH; then DBU, Mel,
  • i HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v: lithium hexamethyldisilazide, THF, -78°, 51 ; vi: Pd/C, H 2 , EtOH; then DBU,
  • i HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v: lithium hexamethyldisilazide, THF, -78°, 59; vi: Pd/C, H 2 , EtOH; then DBU,
  • i HBr; ii: DBU, Mel, DMF; iii: DIBAH, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v: lithium hexamethyldisilazide, THF, -78°, 63 vi: Pd/C, H 2 , EtOH; then DBU,
  • i iBuMgCI.THF; ii: NaH, THF; iii: lithium hexamethyldisilazide, THF, chlorotrimetylsilane, -78°; then R 6 -X; iv: NaOHaq., MeOH, 75°; then HCIaq.; v: DBU, Mel, DMF; vi: lithium hexamethyldisilazide , THF, chlorotrimetylsilane, -78°; then R 1 -X; vii: resolution (e.g.
  • i NaOMe, MeOH; ii: NaH, THF; iii: NaOHaq., MeOH, 75°; then HCIaq.; iv: DBU, Mel, DMF; v: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78°; then R 1 -X; vi: resolution (e.g. lipase); then isolation of methylester: DBU, Mel, DMF; vii: LiOHx1H 2 0, MeOH, H 2 0; viii:TFA,
  • A59 can be prepared according to Scheme 21.
  • i NaOMe, MeOH; ii: NaH, THF; iii: NaOHaq., MeOH, 75°; then HCIaq.; iv: DBU, Mel, DMF; v: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78°; then R 1 -X; vi: resolution (e.g. lipase); then isolation of methylester: DBU, Mel, DMF; vii: LiOHx1 H 2 0, MeOH, H 2 0; viii:TFA,
  • i resolution (e.g. lipase); then DBU, Mel, DMF; ii: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78°; then R 6 -X; iii: LiOHx1 H 2 0, MeOH, H 2 0; iv: TFA, CH 2 CI 2 ; v: FmocOSu,
  • building blocks A70 belong to the class of open-chain ⁇ -substituted ⁇ -amino acids, A71 and A72 to the class of the corresponding ⁇ -amino acid analogues and A73-A104 to the class of the cyclic analogues of A70
  • A73-A104 can be prepared starting from the corresponding ketones 138, hydantoin formation (139) (E Ware, J Chem Res 1950, 46, 403, L H Goodson, I L Honigberg, j j Lehmann, W H Burton, J Org Chem 1960, 25, 1920, S N Rastogi, J S Bindra, N Anand, Ind J Chem 1971, 1 175, D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, He7v Chim Acta 1995, 78, 563-580) and saponification (Ba(O ⁇ ) 2 ) to yield the racemic amino acids 140, which upon Schotten-Baumann-acylation and cyclization with N,N'- dicyclohexylcarbodiimide gave azlactones 141 Reaction with L-phenylalanme cyclohexylamide (D Obrecht, U Bohd
  • A71 Amino acid building blocks of this type can be conveniently prepared from the corresponding disubstituted succinates 146 by C-.r- t.5-rearrangement as shown in Scheme 29 Scheme 29
  • the phthalimide group is cleaved off from the resulting product, conveniently by treatment with hydrazine in a suitable solvent such as ethanol at an elevated temperature, suitably at about 80° C and cleavage of the formed product with tnfluoracetic acid in CH 2 C1 2 vin
  • the formed amino acid is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine m a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 154 as described by Bisang, C , Weber, C , Robinson, J A He7v Chim Acta 1996, 79, 1825-1842
  • n The phthalimide group is cleaved off from the product, conveniently by hydrazmolysis, e.g. by treatment with methylhydrazine in a suitable solvent such as DMF nr
  • a benzoylatmg reagent such as benzoic acid anhydride or benzoylchlo ⁇ de and a base such as triethylamine or
  • i 166 can be synthesized from 165 according to P Waldmeier, "Solid-supported synthesis of highly substituted xanthene-de ⁇ ved templates for the synthesis of ⁇ -tum stabilized cyclic peptide libraries", PhD-thesis, University of Zurich, 1996
  • cleaving the phthalimide group 166 is conveniently submitted to hydrazmolysis, e g by treatment with hydrazine hydrate in a suitable solvent such as ethanol at an elevated temperature, e g at about 80° C n
  • the intermediate aminonit ⁇ le is saponified, conveniently under basic conditions, e g with aqueous sodium hydroxide in a suitable solvent such as ethanol at an elevated temperature, conveniently under reflux, to yield 167
  • Double ortho- brommation of 171 is performed preferably with excess bromine in acetic acid and dichloromethane
  • amino group is protected, conveniently Cbz-protected, with reagents such as benzyloxycarbonyl chloride or succimmide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide
  • the carboxylic acid group is este ⁇ fied, preferably with DBU and methyl iodide in DMF to yield 172
  • R 38 vi For cleaving the benzyloxy group the intermediate is conveniently heated with sodium cyanide adsorbed on aluminum oxide and methanol vii Treatment with an appropriate t ⁇ flating reagent, preferably trifluoromethanesulfonic acid anhydride, in the presence of a base such as 2,6-d ⁇ -tert -butyl-pyndine in a suitable solvent such as dichloromethane via Introduction of lower alkyl and aryl substituents (R 36 ), e g by pallad ⁇ um(O)- catalyzed Stille- (Stille, J K Angew Chem 1986, 68, 504) and Suzuki- couplings (Oh-e, T , Myaura, N ,
  • 3,7-Dimethoxyphenothiazine 186 is prepared and converted into 187 according to Muller, K.; Obrecht, D.; Knierzinger, A.; Spiegler, C; Bannwarth, W.; Trzeciak, A.; Englert, G.; Labhardt, A.; Schonholzer, P. Perspectives in Medicinal Chemistry, Editor Testa, B.; Kyburz, E.; Fuhrer, W.; Giger, R., Weinheim, New York, Basel, Cambridge: Verlag Helvetica Chimica Acta, 1993, 513-531; Bannwarth, W.; Gerber, F.; Grieder, A.; Knierzinger, A.; Muller, K.; Obrecht.
  • the benzyl group is cleaved off from 187 conveniently by hydrogenation, e.g. with H 2 and a catalyst such as palladium on charcoal in a suitable solvent such as ethanol, DMF or ethyl acetate.
  • a catalyst such as palladium on charcoal
  • a suitable solvent such as ethanol, DMF or ethyl acetate.
  • Lower alkyl (R 43 ) by alkylation using an appropriate alkylating agent (R 3 -X'; X - OTf, Br, I) and strong bases such as sodium amide in liquid ammonia or sodium hydride in tetrahydrofuran, dioxan or DMF in the presence of a phase transfer catalyst such as TDA-I.
  • substituted lower alkyl R 43
  • R 43 CH 2 COOR 55 and CH CH 2 COOR 55 can be introduced by treatment with the appropriate 2-halo acetic and, respectively, 3-halo propionic acid derivatives.
  • Any other functionahzation known for diarylamines can be employed for introduction of substituents R 43 .
  • the cyano group of 188 and, respectively, 189 is hydrolyzed, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, e g at about 100° C vi
  • the phthalimide group of the intermediate is cleaved, conveniently by hydrazmolysis, e g with hydrazine hydrate in a suitable solvent such as ethanol vii
  • the free ammo group is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 190 and, respectively, 191 Scheme 39
  • the cyano group of 188 is hydrolyzed, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, e g at about 100° C ii
  • the phthalimide group of the intermediate is cleaved, conveniently by hydrazmolysis, e g with hydrazine hydrate m a suitable solvent such as ethanol to yield 192 m
  • Double ortho- brommation of 192 is performed preferably with excess bromine in acetic acid and dichloromethane
  • Any other functionahzation by electrophilic aromatic substitution known can be employed for introduction of substituents R ' and R 42 iv
  • the amino group is protected, conveniently Cbz-
  • 197 can be prepared from commercial resorufin and coverted into 198 according to Muller, K , Obrecht, D , Knierzinger, A , Spiegler, C , Bannwarth, W , Trquelak, A , Englert, G , Labhardt, A , Schonholzer, P Perspectives in Medicinal Chemistry, Editor Testa, B , Kyburz, E , Fuhrer, W , Giger, R , Weinheim, New York, Basel, Cambridge Verlag Helvetica Chimica Acta, 1993, 513-531, Bannwarth, W , Gerber, F , G ⁇ eder, A , Knierzinger, A , Muller, K , Obrecht D , Trquelak, A Can Pat Appl CA2101599(131 pages)
  • For splitting off the benzyl group 198 is conveniently hydrogenated e g with H 2 and a catalyst such as palladium on charcoal in a suitable solvent such as ethanol, DMF or eth
  • diarylamino groups known can be employed for introduction of substituents R 43 in Cleavage of the methoxy groups of 199, conveniently by treatment with excess boron tnbromide in dichloromethane at temperatures ranging from about -20° to about room temperature iv
  • the intermediate bis-phenol derivative is preferably reacted with R 39 and R 0 -X' (X - OTf, Br,
  • the cyano group of 199 and, respectively, 200 is hydrolyzed under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, conveniently at about 100° C vi-
  • the phthalimide group is cleaved, conveniently by hydrazmolysis, e g with hydrazine hydrate in suitable solvent such as ethanol v ⁇ .
  • the free amino group is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 201 and, respectively, 202
  • reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane
  • the cyano group of 199 is hydrolyzed, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, e g at about 100° C ii
  • the phthalimide group of the intermediate is cleaved, conveniently by hydrazmolysis, e g with hydrazine hydrate in a suitable solvent such as ethanol to yield 203 m
  • Double ortho- brommation of 203 is performed preferably with excess bromine in acetic acid and dichloromethane
  • the amino group is protected, conveniently Cbz-protected
  • Templates(d) can be prepared according to D Obrecht, U Bohdal, C Lehmann, P Schonholzer, K Muller, Tetrahedron 1995, 57, 10883, D Obrecht, C Abrecht, M Altorfer, U Bohdal, A Gneder, M Kleber. P Pfyffer, K Muller, Helv Chim Acta 1996, 79, 1315-1337
  • the ⁇ -hairpin peptidomimetics of the invention can be used in a wide range of applications in order to inhibit the growth of or to kill microorganisms In particular they can be used to selectively inhibit the growth of or to kill microorganisms such as Pseudomonas aeruginosa and Acinetobacter They can be used for example as disinfectants or as preservatives for materials such as foodstuffs, cosmetics, medicaments and other nutnent-containing materials.
  • the ⁇ -hairpin peptidomimetics of the invention can also be used to treat or prevent diseases related to microbial infection m plants and animals
  • the ⁇ -hairpm peptidomimetics can be added to the desired material singly, as mixtures of several ⁇ -hairpin peptidomimetics or in combination with other antimicrobial agents
  • the ⁇ -hairpm peptidomimetics may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well known in the art
  • the ⁇ -hairpin peptidomimetics can be administered singly, as mixtures of several ⁇ -hairpin peptidomimetics, in combination with other antimicrobial or antibiotic agents, or anti
  • compositions comprising ⁇ -hairpin peptidomimetics of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophihzing processes
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active ⁇ - hairpin peptidomimetics into preparations which can be used pharmaceutically Proper formulation depends upon the method of administration chosen
  • ⁇ -hairpin peptidomimetics of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc as are well-known in the art
  • Systemic formulations include those designed for administration by injection, e g subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration
  • the ⁇ -hairpin peptidomimetics of the invention may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hink's solution, Ringer's solution, or physiological saline buffer
  • the solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents
  • the ⁇ -hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e g , sterile pyrogen-free water, before use
  • penetrants appropnate to the barrier to be permeated are used in the formulation as known in the art
  • the compounds can be readily formulated by combining the active ⁇ -hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art Such carriers enable the ⁇ -hairpin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurnes, suspensions etc , for oral ingestion of a patient to be treated
  • suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol, cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrohdone (PVP), granulating agents, and binding agents
  • desintegratmg agents may be added, such as cross-
  • suitable earners, excipients or diluents include water, glycols, oils, alcohols, etc.
  • flavoring agents, preservatives, coloring agents and the like may be added
  • composition may take the form of tablets, lozenges, etc formulated as usual
  • the ⁇ -hairpin peptidomimetics of the invention are conveniently delivered in form of an aeorosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e g dichlorodifluoromethane, t ⁇ chlorofluromethane, carbon dioxide or another suitable gas
  • a suitable propellant e g dichlorodifluoromethane, t ⁇ chlorofluromethane, carbon dioxide or another suitable gas
  • the dose unit may be determined by providing a valve to deliver a metered amount
  • Capsules and cartridges of e g gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the ⁇ -hairpin peptidomimetics of the invention and a suitable powder base such as lactose or starch
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositones together with appropriate suppository bases such as cocoa butter or other glyce ⁇ des
  • the ⁇ -hairpin peptidomimetics of the invention may also be formulated as depot preparations Such long acting formulations may be administered by implantation (e g subcutaneously or intramuscularly) or by intramuscular injection
  • the ⁇ -hairpin peptidomimetics of the invention may be formulated with suitable polymeric or hydrophobic materials (e g as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts
  • ⁇ -hairpin peptidomimetics of the invention may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent Various sustamed-release materials have been established and are well known by those skilled m the art Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed

Abstract

Template-fixed β-hairpin peptidomimetics of the general formula (I), wherein Z is a template-fixed chain of 12 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to selectively inhibit the growth of or to kill microorganisms such as Pseudomonas aeruginosa and Acinetobacter. They can be used as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials, or as medicaments to treat or prevent infections. In a specific embodiment, the template is based on the D-Pro-L-Pro dipeptide. These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.

Description

TEMPLATE-FIXED PEPTIDOMIMETICS WITH ANTIBACTERIAL ACTIVITY
The present invention provides template-fixed β-haιrpιn peptidomimetics incorporating a template- fixed chain of 12 α-amino acid residues which, depending on their positions in the chain, are Gly or Pro, or of certain types, as defined herein below These template-fixed β-hairpin mimetics have a selective antimicrobial activity In addition, the present invention provides efficient synthetic processes by which these compounds can, if desired, be made in parallel library-format These β- hairpin peptidomimetics show improved efficacy, bioavailability, half-life and most importantly a significantly enhanced ratio between antibacterial activity on the one hand, and hemolysis of red blood cells on the other
The growing problem of microbial resistance to established antibiotics has stimulated intense interest in developing novel antimicrobial agents with new modes of action (H Breithaupt, Nat Biotechnol 1999, / 7, 1165-1169) One emerging class of antibiotics is based on naturally occurring catiomc peptides (T Ganz, R I Lehrer, Mol Medicine Today 1999, 5, 292-297, R M Epand, H J Vogel, Biochim Biophys Acta 1999, 1462, 11-28) These include disulfide-bπdged β-hairpm and β-sheet peptides (such as the protegrms [V N M , O V Shamova, H A Komeva, R I Lehrer, FEBS Lett 1993, 327, 231-236], tachyplesins [T Nakamura, H Furunaka, T Miyata, F Tokunaga, T Muta, S Iwanaga, M Niwa, T Takao, Y Shimomshi, Y J Biol Chem 1988, 263, 16709-16713], and the defensins [R I Lehrer, A K Lichtenstein, T Ganz, Annu Rev Immunol 1993, 7 i, 105-128], amphipathic α-helical peptides (e g cecropins, dermaseptins, magamins, and melhtins [A Tossi, L Sandπ, A Giangaspero, Biopolymers 2000, 55, 4-30]), as well as other linear and loop-structured peptides Although the mechanisms of action of antimicrobial catiomc peptides are not yet fully understood, their primary site of interaction is the microbial cell membrane (H W Huang, Biochemistry 2000, 39, 8347-8352) Upon exposure to these agents, the cell membrane undergoes permeabilization, which is followed by rapid cell death However, more complex mechanisms of action, for example, involving receptor-mediated signaling, cannot presently be ruled out (M Wu, E Maier, R Benz, R E Hancock, Biochemistry 1999, 38, 7235-7242)
The antimicrobial activities of many of these catiomc peptides usually correlate with their preferred secondary structures, observed either in aqueous solution or in membrane-like environments (N Sitaram, R Nagaraj, Biochim Biophys Acta 1999, 1462, 29-54) Structural studies by nuclear magnetic resonance (NMR) spectroscopy have shown that catiomc peptides such as protegrin 1 (A Aumelas, M Mangoni, C Roumestand, L Chiche, E Despaux, G Grassy, B Calas, A Chavanieu, A Eur J Biochem 1996, 237, 575-583, R L Fahrner, T Dieckmann, S S L Harwig, R I Lehrer, D Eisenberg, J Feigon, J Chem Biol 1996, 3, 543-550) and tachyplesin I (K Kawano, T Yoneya, T Mιyata, K Yoshikawa, F Tokunaga, Y Terada, S J Iwanaga, S J Biol Chem 1990, 265, 15365- 15367) adopt well defined β-hairpin conformations, due to the constraining effect of two disulfide bridges In protegrin analogues lacking one or both of these disulfide bonds, the stability of the β- hairpm conformation is diminished, and the antimicrobial activity is reduced (J Chen, T J Falla, H J Liu, M A Hurst, C A Fujn, D A Mosca, J R EmbreeD J Loury, P A Radel, C C Chang, L Gu, J C Fiddes, Biopolymers 2000, 55, 88-98, S L Harwig, A Waring, H J Yang, Y Cho, L Tan, R I Lehrer, R J Eur J Biochem 1996, 2 '40, 352-357, M E Mangoni, A Aumelas, P Charnet, C Roumestand, L Chiche, E Despaux, G Grassy, B Calas, A Chavanieu, FEBS Lett 1996, 353, 93- 98, H Tamamura, T Murakami, S Noπuchi, K Sugihara, A Otaka, W Takada, T Ibuka, M Waki, N Tamamoto, N Fujn, Chem Pharm Bull 1995, 43, 853-858) Similar observations have been made in analogues of tachyplesin I (H Tamamura, R Ikoma, M Niwa, S Funakoshi, T Murakami, N Fujn, Chem Pharm Bull 1993, 41, 978-980) and in hairpin-loop mimetics of rabbit defensin NP- 2 (S Thennarasu, R Nagaraj, Biochem Biophys Res Comm 1999, 254, 281 -283) These results show that the β-hairpin structure plays an important role in the antimicrobial activity and stability of these protegrin-hke peptides In the case of the catiomc peptides preferring α-hehcal structures, the amphilihc structure of the helix appears to play a key role in determining antimicrobial activity (A Tossi, L Sandri, A Giangaspero, A Biopolymers 2000, 55, 4-30) Gramicidin S is a backbone-cyclic peptide with a well defined β-hairpm structure (S E Hull, R Karlsson, P Mam, M M Woolfson, E J Dodson, Nature 1978, 275, 206-275) that displays potent antimicrobial activity against gram- positive and gram-negative bacteria (L H Kondejewski, S W Farmer, D S Wishart, R E Hancock, R S Hodges, Int J Peptide Prot Res 1996, 47, 460-466) The high hemolytic activity of gramicidin S has, however, hindered its widespread use as an antibiotic Recent structural studies by NMR have indicated that the high hemolytic activity apparently correlates with the highly amphipathic nature of this cyclic β-hairpm-hke molecule, but that it is possible to dissociate antimicrobial and hemolytic activities by modulating the conformation and amphiphihcity (L H Kondejewski, M Jelokhani- Niaraki, S W Farmer, B Lix, M Kay, B D Sykes, R E Hancock, R S Hodges, J Biol Chem 1999, 274, 13181-13192, C McInnesL H Kondejewski, R S Hodges, B D Sykes, J Biol Chem 2000, 275, 14287-14294)
A new cyclic antimicrobial peptide RTD-1 was reported recently from primate leukocytes (Y -Q Tang, J Yuan, G Osapay, K Osapay, D Tran, C J Miller, A J Oellette, M E Selsted, Science 1999, 286, 498-502 This peptide contains three disulfide bridges, which act to constrain the cyclic peptide backbone into a hairpin geometry Cleavage of the three disulfide bonds leads to a significant loss of antimicrobial activity Analogues of protegrms (J P Tarn, C Wu, J -L Yang, Eur J Biochem 2000, 267, 3289-3300) and tachyplesins (J -P Tam, Y -A Lu, J -L Yang, Biochemistry 2000, 39, 7159-7169, N Sitaram, R Nagaraij, Biochem Biophys Res Comm 2000, 267, 783-790) containing a cyclic peptide backbone, as well as multiple disulfide bridges to enforce a amphiphihc hairpin structure, have also been reported In these cases, removal of all the cystme constraints does not always lead to a large loss of antimicrobial activity, but does modulate the membranolytic selectivity (J P Tam, C Wu, J -L Yang, Eur J Biochem 2000, 267, 3289-3300)
A key issue in the design of new selective catiomc antimicrobial peptides are bioavailability, stability and reduced haemolytic activity The naturally occurring protegrms and tachyplesins exert a significant hemolytic activity against human red blood cells This is also the case for protegrin analogues such as IB367 (J Chen, T J Falla, H J Liu, M A Hurst, C A Fujn, D A Mosca, J R Embree, D J Loury, P A Radel, C C Chang, L Gu, J C Fiddes, Biopolymers 2000, 55, 88-98, C Chang, L Gu, J Chen, US-Pat 5,916,872, 1999) This high hemolytic activity essentially obviates its use in vivo, and represents a serious disadvantage in clinical applications Also, the antibiotic activity of analogues often decreases significantly with increasing salt concentration, such that under in vivo conditions (ca 100-150 mM NaCl) the antimicrobial activity may be severely reduced
Protegrin 1 exhibits potent and similar activity against gram-positive and gram-negative bacteria as well as fungi in both low- and high-salt assays This broad antimicrobial activity combined with a rapid mode of action, and their ability to kill bacteria resistant to other classes of antibiotics, make them attractive targets for development of clinically useful antibiotics The activity against gram- positive bacteria is typically higher than against gram-negative bacteria However, protegrin 1 also exhibits a high hemolytic activity against human red blood cells, and hence a low selectivity towards microbial cells Oriented CD experiments (W T Heller, A J Waring, R I Lehrer, H W Huang, Biochemistry 1998, 37, 17331-17338) indicate that protegrin 1 may exist in two different states as it interacts with membranes, and these states are strongly influenced by lipid composition Studies of cyclic protegrin analogues (J -P Tam, C Wu, J -L Yang, Eur J Biochem 2000, 267, 3289-3300) have revealed, that an increase in the conformational rigidity, resulting from backbone cyclization and multiple disulfide bridges, may confer membranolytic selectivity that dissociates antimicrobial activity from hemolytic activity, at least in the series of compounds studied
Protegrin I is an 18 residues linear peptide, with an amidated carboxyl terminus and two disulfide bridges Tachyplesin I contains 17 residues, also has an amidated carboxyl terminus and contains two disulfide bridges Recently described backbone-cyclic protegrin and tachyplesin analogues typically contain 18 residues and up to three disulfide bridges (J P Tam, C Wu, J -L Yang, Eur J Biochem 2000, 267, 3289-3300, J P Tam, Y -A Lu, J -L Yang, Biochemistry 2000, 39, 7159-7169, N Sitaram, R Nagaraιj, -3.oc .ew Biophys Res Comm 2000, 267, 783-790)
Cαthehcidin , a 37-resιdue linear helical-type catiomc peptide, and analogues are currently under investigation as inhaled therapeutic agents for cystic fibrosis (CF) lung disease (L Saiman, S Tabibi, T D Starner, P San Gabriel, P L Wmokur, H P Jia, P B McGray, Jr , B F Tack, Antimicrob Agents and Chemother 2001, 45, 2838-2844, R E W Hancock, R Lehrer, Trends Biotechnol 1998, 76, 82-88) Over 80% of CF patients become chronically infected with pseudomonas aeruginosa (C A Demko, P J Biard, P B Davies. Clin Epidemiol 1995, 45, 1041-1049, E M Kerem, R Gold, H Levιnson, J Pediatr 1990, 776, 714-719) Other antimicrobial peptides against Pseudomonads
(Y H Yau, B Ho, N S Tan, M L Ng, J L Ding, Antimicrob Agents and Chemother 2001, 45, 2820- 2825 and herein cited references), like FALL-39, SMAP-29, and lepidopteran cecropm display a few of the desired attributes like potent antimicrobial activity over a wide range of pH, rapid killing rate, and low hemolytic activity
In the compounds described below, a new strategy is introduced to stabilize β-hairpin conformations in backbone-cyclic catiomc peptide mimetics exhibiting selective antimicrobial activity This involves transplanting the catiomc and hydrophobic hairpin sequence onto a template, whose function is to restrain the peptide loop backbone into a hairpin geometry
Template-bound hairpin mimetic peptides have been described in the literature (D, Obrecht, M Altorfer, J A Robinson, Adv Med Chem 1999, 4, 1-68, J A Robinson, Syn Lett 2000, 4, 429- 441), but such molecules have not previously been evaluated for development of selective antimicrobial peptides However, the ability to generate β-hairpin peptidomimetics using combinatorial and parallel synthesis methods has now been established (L Jiang, K Moehle, B
Dhanapal, D Obrecht, J A Robinson, Helv Chim Acta 2000, 53, 3097-3112) These methods allow the synthesis and screening of large hairpin mimetic libraries, which in turn considerably facilitates structure-activity studies, and hence the discovery of new molecules with potent selective antimicrobial and very low hemolytic activity to human red blood cells The present strategy allows to synthesize β-hairpin peptidomimetics with novel selectivities towards various multi-drug resistant pseudomonas- or acinetobacter strains
The β-hairpm peptidomimetics of the present invention are compounds of the general formula
(I)
wherein
is a group of one of the formulae
(a1) (a2)
(h) (H) (12)
■3) (14) ϋ)
(n) (o) (P)
wherein
is the residue of an L-α-amino acid with B being a residue of formula -NR20CH(R71)- or the enantiomer of one of the groups Al to A69 as defined hereinafter;
I
is a group of one of the formulae
A1 A2 A3 A4
A5 A6 A7 A8 A9
A10 A11 A12 A13 A14
A21 A22 A23 A24
A25 A26 A27 A28
A29 A30 A31 A32 A33
R1- -N-..,Rό R1-V" ■ *
A38 A39 A40 A41 A42
A43 A44 A45 A46 A47
A53 A54 A55 A56 A57
A58 A59 A60 A61 A62
A63 A64 A65 A66
A84
A80 A81 A82 A83
A95 A96 A97 A98 A99
A100 A101 A102 A103 A104
R1 is H; lower alkyl; or aryl-lower alkyl;
R2 is H; alkyl; alkenyl; -(CH2)m(CHR6')sOR55; -(CH2)m(CHR61)sSR56;
-(CH2)m(CHR6l)sNR33R3V(CH2)m(CHR6')sOCONR33R75;
-(CH2)m(CHR6l)sNR20CONR33R82; -(CH2)o(CHR6')-COOR57;
-(CH2)o(CHR61)sCONR58R59; -(CH2)o(CHR61)sPO(OR60)2;
-(CH2)o(CHR6 l)s S02R62; or -(CH2)0(CHR6,)SC6H4R8; R3 is H; alkyl; alkenyl; -(CH2)m(CHR6l)sOR55; -(CH2)m(CHR6l)sSR56;
-(CH2)m(CHR61 )SNR3 R34; -(CH2)m(CHR61 )sOCONR33R75 ;
-(CH2)„,(CHR6I)SNR20CONR33R82; -(CH2)0(CHR61)sCOOR57 ;
-(CH2)o(CHR61)sCONR58R59 ; -(CH2)o(CHR61)sPO(OR60)2;
-(CH2)0(CHR6,)S S02R62; or -(CH2)0(CHR6,)SC6H4R8; R4 is H; alkyl; alkenyl; -(CH2)m(CHR6 ,)sOR55; -(CH2)m(CHR6')sSR56; -(CH2)m(CHR61)sNR33R34; -(CH2)m(CHR6l)sOCONR33R75; -(CH2)m(CHR6,)sNR20CONR33R82;
-(CH2)P(CHR6 I)SCOOR57; -(CH2)P(CHR6I)SCONR58R59; -(CH2)P(CHR6,)SPO(OR60)2; -(CH2)p(CHR61)s S02R62; or -(CH2)o(CHR6l)sC6H4R8; R5 is alkyl; alkenyl; -(CH2)0(CHR61)sOR55; -(CH2)0(CHR61)SSR56; -(CH2)0(CHR6')SNR33R34; -(CH2)o(CHR61)sOCONR33R75; -(CH2)o(CHR61)sNR20CONR33R82; -(CH2)o(CHR61)sCOOR57; -(CH2)o(CHR61)sCONR58R59; -(CH2)o(CHR61)sPO(OR60)2; -(CH2)o(CHR61)s S02R62; or -(CH2)0(CHR61)SC6H4R8; R6 is H; alkyl; alkenyl; -(CH2)0(CHR61)sOR55; -(CH2)0(CHR6I)SSR56; -(CH2)0(CHR6')SNR33R34; -(CH2)0(CHR6')sOCONR33R75; -(CH2)o(CHR6l)sNR20CONR33R82;
-(CH2)0(CHR61)sCOOR57; -(CH2)o(CHR6')sCONR58R59; -(CH2)o(CHR6l)sPO(OR60)2; -(CH2)0(CHR6,)S S02R62; or -(CH2)0(CHR61)SC6H4R8; R7 is alkyl; alkenyl; -(CH2)q(CHR6l)sOR55; -(CH2)q(CHR61)sNR33R34; -(CH2)q(CHR6 ' )sOCONR33R75 ; -(CH2)q(CHR6 ' )SNR20CONR33R82; -(CH2)r(CHR6,)sCOOR57; -(CH2)r(CHR6l)sCONR58R59; -(CH2)-(CHR6')SPO(OR60)2;
-(CH2)-(CHR6')SS02R62; or -(CH2)r(CHR6l)s C6H4R8; R8 is H; Cl; F; CF ; N02; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl; -(CH2)o(CHR6')s0R55; -(CH2)0(CHR61)SSR56; -(CH2)0(CHR6')NR33R34 ; -(CH2)0(CHR6 ' )sOCONR33R75 ; -(CH2)0(CHR6 ' )SNR20CONR33R82 ; -(CH2)o(CHR61)sCOOR57; -(CH2)0(CHR61)sCONR58R59; -(CH2)o(CHR61)sPO(OR60)2;
-(CH2)0(CHR6')sS02R62; or -(CH2)0(CHR61)sCOR64; R9 is alkyl; alkenyl; -(CH2)0(CHR61)sOR55; -(CH2)0(CHR6')SSR56; -(CH2)0(CHR61)SNR33R34; -(CH2)o(CHR6,)sOCONR33R75; -(CH2)o(CHR61)sNR20CONR33R82; -(CH2)0(CHR6 ' )sCOOR57; -(CH2)0(CHR6 ' )sCONR58R59; -(CH2)0(CHR61 )SPO(OR60)2 ; -(CH2)0(CHR6I)S S02R62; or -(CH2)0(CHR6I)SC6H4R8;
R'° is alkyl; alkenyl; -(CH2)0(CHR6l)sOR55; -(CH2)0(CHR6')SSR56; -(CH2)0(CHR6I)SNR33R34; -(CH2)0(CHR61 )sOCONR33R75 ; -(CH2)0(CHR6 ' )SNR20CONR33R82 ; -(CH2)o(CHR6')sCOOR57; -(CH2)o(CHR6l)-CONR58RS9; -(CH2)o(CHR6l)sPO(OR60)2; -(CH2)0(CHR6')S S02R62; or -(CH2)0(CHR6I)SC6H-.R8; R" is H; alkyl; alkenyl; -(CH2)m(CHR6 l)sOR55; -(CH2)m(CHR6l)sNR33R34; -(CH2)m(CHR6 ')sOCONR33R75; -(CH2)m(CHR61 )SNR20CONR33R82; -(CH2)o(CHR61)sCOOR57; -(CH2)o(CHR61)sCONR58R59; -(CH2)o(CHR5,)sPO(OR60)2; -(CH2)0(CHR(il)sS02R62; or -(CH2)0(CHR61)S H4R8; R12 is H; alkyl; alkenyl; -(CH2)m(CHR6')sOR55; -(CH2)m(CHR61)sSR56; -(CH2)m(CHR61)sNR33R34; -(CH2)„,(CHR6l)sOCONR33R75;
-(CH2),„(CHR61)SNR 0CONR3 R82; -(CH2)r(CHR61)sCOOR57; -(CH2)r(CHR6l)sCONR58R59; - (CH2)r(CHR6l)sPO(OR60)2; -(CH2)r(CHR6,)s S02R62; or -(CH2).(CHR6I)SC6H4R8; R13 is alkyl, alkenyl, -(CH2)q(CHR61)sOR5S, -(CH2)q(CHR61)sSR56, -(CH2)q(CHR61)sNR33R34, -(CH2)q(CHR6l)5OCONR33R75, -(CH2)q(CHR6')sNR20CONR33R82,
-(CH2)q(CHR61)sCOOR57, -(CH2)q(CHR61)sCONR58R59, -(CH2)q(CHR6l)sPO(OR60)2, -(CH2)q(CHR61)s S02R62, or -(CH2)q(CHR61)sC6H4R8, R14 is H, alkyl, alkenyl, -(CH2)m(CHR61)sOR55, -(CH2)m(CHR6l)5NR33R34, -(CH2)m(CHR6')sOCONR33R75, -(CH2)m(CHR61)sNR20CONR33R82, -(CH2)q(CHR6 l)sCOOR57, -(CH2)q(CHR6,)-CONR58R59, -(CH2)q(CHR6l)sPO(OR60)2, -(CH2)q(CHR6')sSOR62, or -(CH2)q(CHR6l)s ILR8, R15 is alkyl, alkenyl, -(CH2)0(CHR61)sOR55, -(CH2)0(CHR6I)SSR56, -(CH2)0(CHR6I)SNR33R34, -(CH2)o(CHR61)sOCONR33R75, -(CH2)o(CHR61)sNR20CONR33R82,
-(CH2)0(CHR61)sCOOR57, -(CH2)0(CHR61)sCONR58R59, -(CH2)o(CHR6l)sPO(OR60)2, -(CH2)„(CHR61)S S02R62, or -(CH2)o(CHR61)sC6H4R8, R16 is alkyl, alkenyl, -(CH2)0(CHR6')sOR55, -(CH2)0(CHR61)SSR56, -(CH2)0(CHR6')SNR33R34, -(CH2)0(CHR6 ' )sOCONR33R75 , -(CH2)0(CHR61 )SNR20CONR33R82 , -(CH2)0(CHR61)sCOOR57, -(CH2)0(CHR6,)sCONR58R59, -(CH2)o(CHR6')sPO(OR60)2,
-(CH2)0(CHR6 I)5 S02R62, or -(CH2)0(CHR61)SC6H4R8, R17 is alkyl, alkenyl, -(CH2)q(CHR6l)sOR55, -(CH2)q(CHR6l)sSR56, -(CH2)q(CHR6')sNR33R34, -(CH2)q(CHR61)sOCONR33R75, -(CH2)q(CHR61)sNR20CONR33R82, -(CH2)q(CHR6 ' )sCOOR57, -(CH2)q(CHR6 ' )sCONR58R59, -(CH2)q(CHR6 ' )SPO(OR60)2 , -(CH2)q(CHR6l)s S02R62, or -(CH2)q(CHR6l)sC6H4R8,
R18 is alkyl, alkenyl, -(CH2)p(CHR61)sOR55, -(CH2)P(CHR51)5SR56, -(CH2)P(CHR6,)SNR33R34, -(CH2)p(CHR6,)sOCONR33R75, -(CH2)P(CHR6,)SNR20CONR33R82, -(CH2)p(CHR6 l)5COOR57, -(CH2)p(CHR61)sCONR58R59, -(CH2)P(CHR6')SPO(OR60)2) -(CH2)p(CHR61)s S02R62, or -(CH2)0(CHR6')SC6H4R8, R19 is lower alkyl, -(CH2)p(CHR6,)sOR55, -(CH2)P(CHR6,)SSR56, -(CH2)P(CHR61)SNR33R34, -(CH2)P(CHR6 ')sOCONR33R75 , -(CH2)P(CHR6 ' )SNR20CONR33R82 , -(CH2)p(CHR6,)sCOOR57, -(CH2)p(CHR6')sCONR58R5 ) -(CH2)p(CHR6')5PO(OR60)2, -(CH2)p(CHR6')s S02R62, or -(CH2)0(CHR6')SC6H4R8, or R18 and R19 taken together can form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-,
R20 is H, alkyl, alkenyl, or aryl-lower alkyl,
R2' is H, alkyl, alkenyl, -(CH2)0(CHR6l)sOR55, -(CH2)0(CHR6I)SSR56, -(CH2)„(CHR6')SNR33R34, -(CH2)0(CHR6 ' )5OCONR33R75 , -(CH2)0(CHR6 ' )SNR20CONR33R82, -(CH2)0(CHR61)sCOOR57, -(CH2)0(CHR6')sCONR58R59, -(CH2)o(CHR6')sPO(OR60)2, -(CH2)0(CHR61)S S02R62, or -(CH2)0(CHR61)SC6H4R8,
R22 is H, alkyl, alkenyl, -(CH2)0(CHR6')SOR55, -(CH2)0(CHR61)SSR56, -(CH2)0(CHR6')SNR33R34, -(CH2)0(CHR6 ' )sOCONR33R7S , -(CH2)0(CHR6 ' )SNR20CONR33R82 , -(CH2)o(CHR6')sCOOR57, -(CH2)o(CHR6l)3CONR58R59, -(CH2)„(CHR6l)3PO(OR60)2, -(CH2)o(CHR6l)s S02R62, or -(CH2)0(CHR61)SC6H4R8, R23 is alkyl, alkenyl, -(CH2)0(CHR61)SOR55, -(CH2)0(CHR61)SSR56, -(CH2)0(CHR61)SNR33R34, -(CH2)o(CHR61)3θCONR33R75, -(CH2)o(CHR61)3NR 0CONR33R82, -(CH2)0(CHR61)sCOOR57, -(CH2)0(CHR6l)sCONR58R59, -(CH2)o(CHR61)sPO(OR60)2,
-(CH2)0(CHR6I)S S02R62, or -(CH2)0(CHR6,)SC6H4R8, R24 is alkyl, alkenyl, -(CH2)0(CHR6l)sOR55, -(CH2)o(CHR6l)sSR56, -(CH2)0(CHR6I)SNR33R34, -(CH2)0(CHR6,)sOCONR33R75, -(CH2)o(CHR61)sNR20CONR33R82, -(CH2)0(CHR6I)SCOOR57, -(CH2)0(CHR6l)sCONR58R59, -(CH2)o(CHR6')sPO(OR60)2, -(CH2)0(CHR6I)S S02R62, or -(CH2)0(CHR61)SC6H4R8,
R25 is H, alkyl, alkenyl, -(CH2)m(CHR6 l)sOR55, -(CH2)m(CHR6')sSR56, -(CH2)m(CHR6l)sNR33R34, -(CH2)m(CHR6l)sOCONR33R75, -(CH2)m(CHR61)sNR20CONR33R82, -(CH2)o(CHRδ')sCOOR57, -(CH2)o(CHR61)sCONR58R59, -(CH2)o(CHR61)sPO(OR60)2, -(CH2)o(CHR61)sS02R62, or -(CH2)0(CHR61)SC6H4R8,
R26 is H, alkyl, alkenyl, -(CH2)m(CHR61)sOR55, -(CH2)m(CHR61)sSR56, -(CH2)m(CHR61)sNR33R34, -(CH2)m(CHR61)sOCONR33R75,
-(CH2)m(CHR6')sNR20CONR33R82, -(CH2)0(CHR6')SCOOR57, -(CH2)0(CHR6')sCONR58R59, - (CH2)0(CHR6,)SPO(OR60)2, -(CH2)0(CHR61)S S02R62, or -(CH2)o(CHR61)sC6H4R8, or
R25 and R26 taken together can form -(CH2)2 6-, -(CH2)rO(CH2)r-, -(CH2)rS(CH2)r-, or
-(CH2)rNR57(CH2)r-, R27 is H, alkyl, alkenyl, -(CH2)0(CHR6')sOR55, -(CH2)0(CHR6I)SSR56, -(CH2)0(CHR6')SNR33R34, -(CH2)0(CHR61)sCO0R57 > -(CH2)o(CHR6')sC0NR58R59, -(CH2)o(CHR61)s0C0NR33R75, -(CH2)o(CHR6l)3NR20CONR33R82, -(CH2)0(CHR6 I)SPO(OR60)2,
-(CH2)0(CHR61)S S02R62, or -(CH2)0(CHR6')SC6H4R8, R28 is alkyl, alkenyl, -(CH2)0(CHR61)s-OR55, -(CH2)0(CHR61)S SR56, -(CH2)0(CHR6I)S NR33R34, -(CH2)0(CHR61)sOCONR33R75, -(CH2)o(CHR61)sNR20CONR33R82, -(CH2)0(CHR61)S COOR57, -(CH2)0(CHRδ')s CONR58R59, -(CH2)0(CHR61)S PO(OR60)2, -(CH2)0(CHR61)S S02R62, or -(CH2)0(CHR6,)S QΛR8,
R29 is alkyl, alkenyl, -(CH2)0(CHR6l)-OR55, -(CH2)0(CHR6I)SSR56, -(CH2)o(CHR6l)sNR33R34, -(CH2)o(CHR61)sOCONR33R75, -(CH2)o(CHR6l)sNR20CONR33R82, -(CH2)0(CHR6l)sCOOR57, -(CH2)o(CHR6l)sCONR58R59, -(CH2)o(CHR6l)sPO(OR60)2, -(CH2)0(CHR61)S S02R62, or -(CH2)0(CHR6,)SC6H4R8, R30 is H, alkyl, alkenyl, or aryl-lower alkyl,
R31 is H, alkyl, alkenyl, -(CH2)p(CHR )5OR55, -(CH2)P(CHR6')SNR33R34, -(CH2)p(CHR6')sOCONR33R75, -(CH2)p(CHR6l)-NR20CONR33R82, -(CH2)o(CHR6')sCOOR57; -(CH2)o(CHR6l)-CONR58R59; -(CH2)o(CHR61)sPO(OR60)2; -(CH2)0(CHR61)-S02R62; or -(CH2)0(CHR61)S C6H4R8; R32 is H; lower alkyl; or aryl-lower alkyl;
R33 is H; alkyl, alkenyl; -(CH2)m(CHR61)sOR55; -(CH2)m(CHR6')sNR34R63; -(CH2)m(CHR6')sOCONR75R82; -(CH2)m(CHR6,)sNR20CONR78R82;
-(CH2)o(CHR61)sCOR6 ; -(CH2)o(CHR61)s-CONR58R59, -(CH2)o(CHR61)sPO(OR60)2; -(CH2)0(CHR6 I)S S02R62; or -(CH2)0(CHR61)SC6H4R8; R34 is H; lower alkyl; aryl, or aryl-lower alkyl;
R33 and R34 taken together can form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-;
R35 is H; alkyl; alkenyl; -(CH2)m(CHR6')s0R55; -(CH2)m(CHR6l)5NR33R34; -(CH2)„,(CHR6 ' )s0C0NR33R75; -(CH2)m(CHR6 ' )SNR20CONR33R82; -(CH2)p(CHR6')sCOOR57; -(CH2)p(CHR61)sCONR58R59; -(CH2)p(CHR6')sPO(OR60)2; -(CH2)P(CHR61)sS02R62; or -(CH2)P(CHR6,)S H.R8; R36 is H, alkyl; alkenyl; -(CH2)0(CHR61)sOR55; -(CH2)P(CHR61)SNR33R34; -(CH2)P(CHR6 ' )sOCONR33R75 ; -(CH2)P(CHR6 ' )SNR20CONR33R82; -(CH2)p(CHR61)sCOOR57; -(CH2)p(CHR61)sCONR58R59; -(CH2)p(CHR6l)sPO(OR60)2; -(CH2)p(CHR6,)sS02R62; or -(CH2)0(CHR6')S QftR8; R37 is H; F; Br; Cl; N02; CF3; lower alkyl; -(CH2)p(CHR6l)sOR55; -(CH2)P(CHR6,)SNR33R34; -(CH2)P(CHR61)sOCONR33R75; -(CH2)P(CHR61)SNR20CONR33R82;
-(CH2)0(CHR6l)sCOOR57; -(CH2)0(CHR6l)sCONR58R59; -(CH2)o(CHR6l)sPO(OR60)2; -(CH2)0(CHR6 l)sS02R62; or -(CH2)0(CHR6,)S C6H4R8; R38 is H; F; Br; Cl; N02; CF3; alkyl; alkenyl; -(CH2)p(CHR6')sOR55; -(CH2)P(CHR6')SNR33R34; -(CH2)P(CHR6')SOCONR33R75; -(CH2)P(CHR6')SNR20CONR33R82; -(CH2)o(CHR6')sCOOR57; -(CH2)0(CHR6')sCONR 8R59; -(CH2)o(CHR6')sPO(OR60)2;
-(CH2)0(CHR6,)sS02R62; or -(CH2)0(CHR6I)SC6H4R8; R39 is H; alkyl; alkenyl; or aryl-lower alkyl; R is H; alkyl; alkenyl; or aryl-lower alkyl;
R4' is H; F; Br; Cl; N02; CF3; alkyl; alkenyl; -(CH2)P(CHR61)S0R55; -(CH2)P(CHR6')SNR33R34; -(CH2)p(CHR6 l)sOCONR33R75; -(CH2)P(CHR61)SNR20CONR33R82;
-(CH2)o(CHR61)sCO0R57; -(CH2)0(CHR61)sCONR58R59; -(CH2)0(CHR6,)sPO(OR60)2; -(CH2)0(CHR6l)sS02R62; or -(CH2)0(CHR61)S C6H4R8; R42 is H; F; Br; Cl; N02; CF3; alkyl; alkenyl; -(CH2)p(CHR6,)sOR55; -(CH2)P(CHR6')SNR33R34; -(CH2)P(CHR6 ' )sOCONR33R75 ; -(CH2)P(CHR6 ' )SNR20CONR33R82; -(CH2)o(CHR6 l)sCOOR57; -(CH2)0(CHR6l)sCONR58R59; -(CH2)0(CHR6I)SPO(OR60)2;
-(CH2)o(CHR6')sS02R62; or -(CH2)0(CHR6')S C6H4R8; R43 is H; alkyl; alkenyl; -(CH2)m(CHR6l)sOR55; -(CH2),n(CHR6l)sNR33R34; -(CH2)m(CHR6 ' )sOCONR33R75 ; -(CH2)m(CHR61 )SNR20CONR33R82; -(CH2)o(CHR6l)sCOOR57; -(CH2)o(CHR6l)sCONR58R59; -(CH2)o(CHR6l)sPO(OR60)2; -(CH2)0(CHR6 l)sS02R62; or -(CH2)0(CHR6')5 H4R8; R44 is alkyl; alkenyl; -(CH2)r(CHR6')sOR55; -(CH2)r(CHR61)-SR56; -(CH2)r(CHR6')sNR33R34; -(CH2)r(CHR6')sOCONR33R75; -(CH2)r(CHR6l)sNR20CONR33R82;
-(CH2)r(CHR6')sCOOR57; -(CH2)r(CHR6l)sCONR58R59; -(CH2).(CHR61)sPO(OR60)2; -(CH2)r(CHR6l)5 S02R62; or -(CH2)r(CHR6,)sC6H4R8; R45 is H; alkyl; alkenyl; -(CH2)0(CHR6l)sOR55; -(CH2)0(CHR61)SSR56; -(CH2)0(CHR6I)SNR33R34; -(CH2)o(CHR61)sOCONR33R75; -(CH2)o(CHR61)sNR20CONR33R82; -(CH2)0(CHR61)sCOOR57; -(CH2)s(CHR61)sCONR58R59; -(CH2)S(CHR61)SPO(OR60)2;
-(CH2)S(CHR6I)S S02R62; or -(CH2)S(CHR61)SC6H4R8; R46 is H; alkyl; alkenyl; or -(CH2)0(CHR6')PC6H4R8; R47 is H; alkyl; alkenyl; or -(CH2)0(CHR6l)sOR55; R4 is H; lower alkyl; lower alkenyl; or aryl-lower alkyl; R49 is H; alkyl; alkenyl; -(CHR6l)sCOOR57; (CHR5')sCONR58R59; (CHR6')SPO(OR60)2; -(CHR6l)sSOR62; or -(CHR61)SC6H4R8; Rso is H; lower alkyl; or aryl-lower alkyl;
R51 is H; alkyl; alkenyl; -(CH2)m(CHR6')sOR5S; -(CH2)m(CHR6l)sSR56; -(CH2)m(CHR6')sNR33R34; -(CH2)m(CHR6l)sOCONR33R75; -(CH2)rn(CHR6')-NR20CONR3 R82; -(CH2)0(CHR6l)sCOOR57;
-(CH2)o(CHR6 l)sCONR5 R59; -(CH2)o(CHR6l)pPO(OR60)2; -(CH2)p(CHR61)s S02R62; or -(CH2)P(CHR61)SC6H4R8; R52 is H; alkyl; alkenyl; -(CH2)m(CHR61)sOR55; -(CH2)m(CHR6,)sSR56; -(CH2)m(CHR6 ' )SNR33R34; -(CH2)m(CHR6 ' )SOCONR33R75 ; -(CH2)m(CHR6')sNR20CONR33R82; -(CH2)0(CHR61)sCOOR57;
-(CH2)0(CHR6 ' )sCONR58R59; -(CH2)0(CHR6 ' )PPO(OR60)2; -(CH2)P(CHR61)S S02R62; or -(CH2)P(CHR61)SC6H4R8; R53 is H; alkyl; alkenyl; -(CH2)m(CHR6l)sOR55; -(CH2)m(CHR6l)sSR56; -(CH2)m(CHR6l)sNR33R34; - (CH2)„,(CHR6')sOCONR33R75; -(CH2)m(CHR6l)sNR20CONR33R82; -(CH2)o(CHR61)sC00R57;
-(CH2)o(CHR6l)sCONR58R59; -(CH2)o(CHR6l)pPO(OR60)2; -(CH2)P(CHR6,)S S02R62; or -(CH2)P(CHR6,)SC6H4R8; R54 is H; alkyl; alkenyl; -(CH2)m(CHR6')sOR55; -(CH2)-n(CHR6')sNR33R34; -(CH2)m(CHR61)sOCONR33R75; -(CH2)n,(CHR61)-NR 0CONR33R82; -(CH2)o(CHR6 l)COOR57; -(CH2)0(CHR6,)sCONR58R59; or -(CH2)0(CHR61)S C6H4R8;
R55 is H; lower alkyl; lower alkenyl; aryl-lower alkyl; -(CH2)m(CHR6')sOR57; -(CH2)m(CHR6')sNR34R63; -(CH2)m(CHR6l)-OCONR75R82; -(CH2)m(CHR6l)sNR20CONR78R82, -(CH2)„(CHR6')s-COR64, -(CH2)0(CHR61)COOR57, or -(CH2)0(CHR6')SCONR58R59, R56 is H, lower alkyl, lower alkenyl, aryl-lower alkyl, -(CH2)m(CHR61)sOR57, -(CH2),„(CHR6 ' )SNR34R63 , -(CH2),„(CHR61 )sOCONR75R82 , -(CH2),„(CHR6')SNR20CONR78R82, -(CH2)0(CHR6 l)5-COR64, or
-(CH2)0(CHRc")sCONR58R59 ) R57 is H, lower alkyl, lower alkenyl, aryl lower alkyl, or heteroaryl lower alkyl, R58 is H, lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, or heteroaryl-lower alkyl, R is H, lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, or heteroaryl-lower alkyl, or R58 and R59 taken together can form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, R60 is H, lower alkyl, lower alkenyl, aryl, or aryl-lower alkyl,
R61 is alkyl, alkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, -(CH2)„,OR55, -(CH2)n,NR33R34, -(CH2)mOCONR75R82, -(CH2)mNR20CONR78R82, -(CH2)0COOR37, -(CH2)0NR58R59, or -(CH2)oPO(COR60)2,
R * is lowei alkyl, lower alkenyl, aryl, heteroaryl, or aryl-lower alkyl,
R63 is H, lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl,
-COR64, -COOR57, -CONR58R59, -SO,R62, or -PO(OR60)2, R34and R03 taken together can form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-,
R64 is H, lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, -(CH2)p(CHR<")sOR65, -(CH2)P(CHR6 I)SSR66, or -(CH2)P(CHR6I)-NR34R63, -(CH2)P(CHR6l)sOCONR75R82, -(CH2)p(CHR6l)sNR20CONR78R82, R65 is H, lower alkyl, lower alkenyl, aryl, aryl-lower alkyl, heteroaryl-lower alkyl, -COR57, -COOR57, or -CONR58R59,
R66 is H, lower alkyl, lower alkenyl, aryl, aryl-lower alkyl, heteroaryl-lower alkyl, or
-CONRS8RS9, m is 2-4, o is 0-4, p is 1-4, q is 0-2, r is 1 or 2, s is 0 or 1 ,
Z is a chain of 12 α-amino acid residues, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, whereby these amino acid residues are, depending on their position in the chain, Gly or Pro, or of formula -A-CO-, or of formula -B-CO-, or of one of the types
C NR20CH(R72)CO-, D -NR20CH(R73)CO-, E -NR20CH(R74)CO-, F -NR20CH(R84)CO-,
H -NR20-CH(CO-)-(CH2)4 7-CH(CO-)-NR20-,
-NR20-CH(CO-)-(CH2)pSS(CH2)p-CH(CO-)-NR20-, -NR20-CH(CO-)-(-(CH2)pNR20CO(CH2)p-CH(CO-)-NR20-, and -NR20-CH(CO-)-(-(CH2)pNR 0CONR20(CH2)p-CH(CO-)-NR20-,
R71 is H, lower alkyl, lower alkenyl, -(CH2)p(CHR6,)sOR75, -(CH2)p(CHR6,)sSR75,
-(CH2)P(CHR61)SNR33R34, -(CH2)p(CHR61)sOCONR33R75, -(CH2)P(CHR6')SNR20CONR33R82, -(CH2)0(CHR6l)sCOOR75, -(CH2)PC0NR58R59, -(CH2)pPO(OR62)2, -(CH2)pS02R62, or -(CH2)o-C6R67R68R69R70R76, R72 is H, lower alkyl, lower alkenyl, -(CH2)p(CHR6')sOR85, or -(CH2)P(CHR6')SSR85, R73 is -(CH2)0R77, -(CH2)rO(CH2)oR77, -(CH2)rS(CH2)0R77, or -(CH2)rNR20(CH2)oR77, R74 is -(CH2)PNR78R79, -(CH2)PNR77R80, -(CH2)PC(=NR80)NR 8R79, -(CH2)PC(=NOR50)NR78R79, -(CH2)PC(=NNR78R79)NR78R79, -(CH2)PNR80C(=NR80)NR78R79, -(CH2)pN=C(NR78R80)NR79R80,-(CH2)pC6H4NR78R79, -(CH2)pC6H4NR77R80, -(CH2)PC6H4C(=NR80)NR78R79, -(CH2)PC6H4C(=NOR50)NR78R79,
-(CH2)PC6H4C(=NNR78R79)NR78R79, -(CH2)PC6H4NR80C(=NR80)NR78R79, -(CH2)pC6H4N=C(NR78R80)NR79R80, -(CH2)rO(CH2)mNR78R79, -(CH2)rO(CH2)mNR77R80, -(CH2)rO(CH2)pC(=NR80)NR78R79, -(CH2)rO(CH2)pC(=NORS0)NR78R79, -(CH2)rO(CH2)pC(=NNR78R79)NR78R79, -(CH2)-O(CH2)nιNR80C(=NR80)NR78R79, -(CH2).O(CH2)mN=C(NR78R80)NR79R80, -(CH2)-0(CH2)pC6H4CNR78R79,
-(CH2)rO(CH2)pC6H4C(=NR80)NR78R79, -(CH2)rO(CH2)pC6H4C(=NOR50)NR78R79, -(CH2)rO(CH2)pC6H4C(=NNR78R79)NR78R79,
-(CH2)rO(CH2)pC6H4NR80C(=NR80)NR78R79, -(CH2)rS(CH2)mNR78R79, -(CH2)rS(CH2)mNR77R80,-(CH2).S(CH2)pC(=NR80)NR78R79, -(CH2)rS(CH2)pC(=NOR50)NR78R79, -(CH2)rS(CH2)pC(=NNR78R79)NR78R79,
-(CH2)rS(CH2)nιNR80C(=NR80)NR78R79, -(CH2)-S(CH2)mN=C(NR78R80)NR79R80, -(CH2)rS(CH2)pC6H4CNR78R79, -(CH2)rS(CH2)pC6H4C(=NR80)NR78R79, -(CH2)-S(CH2)pC6H4C(=NOR50)NR78R79, -(CH2)rS(CH2)pC6H4C(=NNR78R79)NR78R79, -(CH2)rS(CH2)pC6H4NR80C(=NR80)NR78R79, -(CH2)pNR80COR64, -(CH2)PNR80COR77, -(CH2)PNR80CONR78R79, or -(CH2)PC6H4NR80CONR78R79,
R75 is lower alkyl, lower alkenyl, or aryl-lower alkyl, R33 and R75 taken together can form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or
-(CH2)2NR57(CH2)2-, R75 and R82 taken together can form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or
R76 is H, lower alkyl, lower alkenyl, aryl-lower alkyl, -(CH2)00R72, -(CH2)0SR72, -(CH2)0NR33R34, -(CH2)00C0NR33R75, -(CH2)oNR20CONR33R82, -(CH2)0COOR75; -(CH2)0CONR58R59; -(CH2)oPO(OR60)2; -(CH2)pS02R62; or -(CH2)0COR64;
R" is -C6R6/R68R69R'UR76; or a heteroaryl group of one of the formulae
H1 H2 H3 H4 H5
H6 H7 H8 H9 H10
H11 H12 H13 H14 H15
H16 H17 H18 H19 H20
H21 H22 H23 H24 H25
H26 H27 H28 H29
H30 H31 H32 H33
H34 H35 H36 H37
H42 H43 H44 H45
H46 H47 H48 H49
R78 is H; lower alkyl; aryl; or aryl-lower alkyl;
R78 and R82 taken together can form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; R is H; lower alkyl; aryl; or aryl-lower alkyl; or
R78 and R79, taken together, can be -(CH2)2.7-; -(CH2)20(CH2)2-; or -(CH2)2NR57(CH2)2-; R80 is H; or lower alkyl; R81 is H, lower alkyl, or aryl-lower alkyl, R82 is H, lower alkyl, aryl, heteroaryl, or aryl-lower alkyl,
R33 and R82 taken together can form -(CH2)2.6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NRS (CH2)2-, R83 ιs H, lower alkyl, aryl, or -NR78R79,
R84 is -(CH2)m(CHR6l)sOH, -(CH2)pCONR78R79, -(CH2)PNR80CONR78R79, -(CH2)pC6H4CONR78R79, or -
(CH2)PC6H4NR80CONR78R79 , R85 is lower alkyl, or lower alkenyl,
with the proviso that in said chain of 12 α-amino acid residues Z the ammo acid residues m positions 1 to 12 are
P 1 of type C or of type D or of type E or of type F, or the residue is Pro, P2 of type D,
P3 of type C, or of type D, or the residue is Pro, - P4 of type C, or of type D, or of type E,
P5 of type E, or of type D, or of type C, or of type F, or the residue is Gly or Pro, P6 of type E, or of type F or of formula -A-CO-, or the residue is Gly, P7 of type C, or of type E or of type F or of formula -B-CO-, P8 of type D, or of type C, or of type F, or the residue is Pro, - P9 of type C, or of type E or of type D or of type F,
P10 of type F, or of type D or of type C, or the residue is Pro, Pl l of type E or of type D or of type C or of type F, and PI 2 of type C or of type D or of type E or of type F, or the residue is Pro, or P4 and P9 and/or P2 and PI 1, taken together, can form a group of type H, and at P6 and P7 also D-isomers being possible, with the further proviso that the amino acid residue in P4 is of type C, and/or the amino acid residue in P5 is of type F, and/or the ammo acid residue m P7 is of type C, and/or - the amino acid residue in P8 is of type F, and or the amino acid residue in P9 is of type C, and/or the amino acid residue in PI 0 is of type F, and/or the amino acid residue in PI 1 is of type C or of type F, and pharmaceutically acceptable salts thereof
In accordance with the present invention these β-hairpin peptidomimetics can be prepared by a process which comprises (a) coupling an appropriately functionahzed solid support with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 5, 6 or 7, any functional group which may be present in said N-protected ammo acid derivative being likewise appropriately protected,
(b) removing the N-protecting group from the product thus obtained,
(c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position nearer the N-terminal amino acid residue, any functional group which may be present in said N-protected ammo acid derivative being likewise appropriately protected,
(d) removing the N-protecting group from the product thus obtained,
(e) repeating steps (c) and (d) until the N-terminal amino acid residue has been introduced,
(f) coupling the product thus obtained with a compound of the general formula
wherein
is as defined above and X is an N-protectmg group or, if
is to be group (al) or (a2), above, alternatively (fa) coupling the product obtained in step (e) with an appropriately N-protected derivative of an amino acid of the general formula
HOOC-B-H III or HOOC-A-H IV wherein B and A are as defined above , any functional group which may be present in said N- protected amino acid derivative being likewise appropπately protected, (fb) removing the N-protecting group from the product thus obtained, and
(fc) coupling the product thus obtained with an appropπately N-protected derivative of an amino acid of the above general formula IV and, respectively, III, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected, (g) removing the N-protecting group from the product obtained in step (f) or (fc), (h) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 12, any functional group which may be present m said N-protected amino acid derivative being likewise appropriately protected, (I) removing the N-protecting group from the product thus obtained,
(j) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected, (k) removing the N-protecting group from the product thus obtained,
(1) repeating steps (j) and (k) until all amino acid residues have been introduced,
(m) if desired, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated,
(o) detaching the product thus obtained from the solid support, (p) cychzing the product cleaved from the solid support,
(q) if desired, forming one or two interstrand hnkage(s) between side-chains of appropriate amino acid residues at opposite positions of the β-strand region,
(r) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule, and
(s) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt
Alternatively, the peptidomimetics of the present invention can be prepared by
(a') coupling an appropriately functionahzed solid support with a compound of the general formula
Template wherein
is as defined above and X is an N-protectmg group or, if s to be group (al) or (a2), above, alternatively
(a'a) coupling said appropriately functionahzed solid support with an appropπately N- protected derivative of an amino acid of the general formula HOOC-B-H III or HOOC-A-H IV wherein B and A are as defined above , any functional group which may be present in said N- protected ammo acid derivative being likewise appropπately protected, (a'b) removing the N-protecting group from the product thus obtained, and (a'c) coupling the product thus obtained with an appropriately N-protected derivative of an amino acid of the above general formula IV and, respectively, III, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected, (b') removing the N-protecting group from the product obtained in step (a') or (a'c), (c') coupling the product thus obtained with an appropriately N-protected derivative of that ammo acid which in the desired end-product is in position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected, (d') removing the N-protecting group from the product thus obtained,
(e') coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected,
(f ) removing the N-protecting group from the product thus obtained, (g') repeating steps (e') and (f ) until all amino acid residues have been introduced, (h') if desired, selectively deprotectmg one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated, (ι') detaching the product thus obtained from the solid support, (]') cychzing the product cleaved from the solid support,
(k') if desired forming one or two interstrand hnkage(s) between side-chains of appropriate amino acid residues at opposite positions of the β-strand region, (I1) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may m addition be present in the molecule, and (m') if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt
The peptidomimetics of the present invention can also be enantiomers of the compounds of formula I These enantiomers can be prepared by a modification of the above processes m which enantiomers of all chiral starting materials are used
As used in this descπption, the term "alkyl", taken alone or in combinations, designates saturated, straight-chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms Similarly, the term "alkenyl" designates straight chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds The term "lower" designates radicals and compounds having up to 6 carbon atoms Thus, for example, the term "lower alkyl" designates saturated, straight-chain or branched hydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert -butyl and the like The term "aryl" designates aromatic carbocyc c hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be substituted by up to three substituents such as Br, Cl, F, CF3, N02, lower alkyl or lower alkenyl The term "heteroaryl" designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to three heteroatoms selected from the group consisting of O, S and N and said rιng(s) being optionally substituted, representative examples of such optionally substituted heteroaryl radicals are indicated hereinabove in connection with the definition of R77
The structural element -A-CO- designates ammo acid building blocks which in combination with the structural element -B-CO- form templates (al) and (a2) Templates (a) through (p) constitute building blocks which have an N-termmus and a C-terminus oriented in space in such a way that the distance between those two groups may he between 40-5 5A A peptide chain Z is linked to the C-termmus and the N-terminus of the templates (a) through (p) via the corresponding N- and C-termim so that the template and the chain form a cyclic structure such as that depicted in formula I. In a case as here where the distance between the N- and C- termini of the template lies between 40-5 5 A the template will induce the H-bond network necessary for the formation of a β-hairpin conformation in the peptide chain Z Thus template and peptide chain form a β-hairpin mimetic
The β-hairpin conformation is highly relevant for the antibiotic activity of the β-hairpin mimetics of the present invention The β-hairpin stabilizing conformational properties of the templates (a) through (p) play a key role not only for the selective antimicrobial activity but also for the synthesis process defined hereinabove, as incorporation of the templates at the beginning of the linear protected peptide precursors enhance significantly cyclization yields
Building blocks A1-A69 belong to a class of amino acids wherein the N-terminus is a secondary amine forming part of a ring Among the genetically encoded amino acids only proline falls into this class The configuration of building block Al through A69 is (D), and they are combined with a building block -B-CO- of (L)-configuratιon Preferred combinations for templates (al) are-DAl-CO- LB-CO- to DA69-CO-LB-CO- Thus, for example, DPro-LPro constitutes the prototype of templates (al) Less preferred, but possible are combinations where templates (a2) are -' Al-CO-DB-CO- to LA69-CO-DB-CO- Thus, for example, LPro-DPro constitutes a less preferred prototype of template (a2)
It will be appreciated that building blocks -Al-CO- to -A69-CO- in which A has (D)-confιguratιon, are caπying a group R1 at the α-position to the N-teπmnus The prefeπed values for R1 are H and lower alkyl with the most preferred values for R1 being H and methyl It will be recognized by those skilled in the art, that A1-A69 are shown in (D)-confιguratwn which, for R' being H and methyl, corresponds to the (R)-configuratιon Depending on the pπoπty of other values for R' according to the Cahn, Ingold and Prelog-rules, this configuration may also have to be expressed as (S)
In addition to R1 building blocks -Al-CO- to -A69-CO- can carry an additional substituent designated as R2 to R17 This additional substituent can be H, and if it is other than H, it is preferably a small to medium-sized aliphatic or aromatic group Examples of preferred values for R2 to R17 are R: H, lower alkyl, lower alkenyl, (CH2)mOR55 (where R55 lower alkyl, or lower alkenyl), (CH2)nlSR56 (where R56 lower alkyl, or lower alkenyl), (CH2),„NR33R34 (where R33 lower alkyl, or lower alkenyl, R34 H, or lower alkyl, R33 and R34 taken together form
-(CH2)2 o-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, R57 H, or lower alkyl), (CH2)n,OCONR33R75 (where R33 H, or lower alkyl, or lower alkenyl, R75 lower alkyl, or R33 and R75 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)mNR 0CONR 3R82 (where R20 H, or lower lower alkyl, R33 H, or lower alkyl, or lower alkenyl, R82 H, or lower alkyl, or R33 and R82 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2),S(CH2)2-, or
-(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oN(R20)COR64(where R20 H, or lower alkyl, R64 lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 lower alkyl, or lower alkenyl, and R59 H, or lower alkyl, or R58 and R59 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-,
-(CH2)2S(CH2) > or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oPO(OR60)2 (where R60 lower alkyl, or lower alkenyl), -(CH2)oS02R62 (where R62 lower alkyl, or lower alkenyl), or -(CH2)qC6Ii,R8 (where R8 H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy)
R3 H, lower alkyl, lower alkenyl, -(CH2)mOR55 (where R55 lower alkyl, or lower alkenyl), - (CH2)mSR56 (where R56 lower alkyl, or lower alkenyl), -(CH2)mNR33R34 (where R33 lower alkyl, or lower alkenyl, R34 H, or lower alkyl, or R33 and R34 taken together form -(CH2)2 6-, -(CH2)20(CH2)2- , -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)mOCONR33R75 (where R33 H, or lower alkyl, or lower alkenyl, R75 lower alkyl, or R33 and R75 taken together fonn - (CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or
-(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2),,,NR20CONR33R82 (where R20 H, or lower lower alkyl, R33 H, or lower alkyl, or lower alkenyl, R82 H, or lower alkyl, or R33 and R82 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or
-(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oN(R20)COR64 (where R20 H, or lower alkyl, R64 lower alkyl, or lower alkenyl), -(CH )0COOR57 (where R57 lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 lower alkyl, or lower alkenyl, and R59 H, lower alkyl, or R58 and R59 taken together form -(CH2)2 b-, -(CH2)20(CH2)2-,
-(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), (CH2)oPO(OR60)2 (where R60 lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 lower alkyl, or lower alkenyl), or - (CH )qC6H4R8 (where R8 H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy)
R' H, lower alkyl, lower alkenyl, -(CH2)mOR55 (where R55 lower alkyl, or lower alkenyl), - (CH2)mSR56 (where R56 lower alkyl, or lower alkenyl), -(CH2)„,NR33R34 (where R33 lower alkyl, or lower alkenyl, R34 H, or lower alkyl, or R33 and R34 taken together form -(CH2)2 <,-, -(CH2).0(CH2)2- , -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2),-, where R57 H, or lower alkyl), -(CH2)mOCONR33R75 (where R33 H, or lower alkyl, or lower alkenyl, R75 lower alkyl, or R33 and R75 taken together form - (CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)mNR20CONR33R82 (where R20 H, or lower lower alkyl, R33 H, or lower alkyl, or lower alkenyl, R82 H, or lower alkyl, or R33 and R82 taken together fonn -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or
-(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)mN(R20)COR64(where R20 H, or lower alkyl, RM lower alkyl, or lower alkenyl), -(CH2)0COORS7 (where R57 lower alkyl, or lower alkenyl), -(CH2)oC0NR58R59 (where R58 lower alkyl, or lower alkenyl, and R59 H, or lower alkyl, or R58 and R59 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-,
-(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oPO(OR60)2 (where R60 lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 lower alkyl, or lower alkenyl), or - (CH2)qC6H4R8 (where R8 H, F, Cl, CF3, lower alkyl, lower alkenyl,or lower alkoxy) - Rs lower alkyl, lower alkenyl, -(CH2)0OR55 (where R55 lower alkyl, or lower alkenyl), -
(CH2)0SR56 (where R56 lower alkyl, or lower alkenyl), -(CH2)0NR33R34 (where R33 lower alkyl, or lower alkenyl, R34 H, or lower alkyl, or R33 and R34 taken together form -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0OCONR33R7S (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)M-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; R57: where H; or lower alkyl); (CH2)oNR 0CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NRS7(CH2)2-; where R57: H; or lower alkyl); (CH2)oN(R20)COR64(where: R20: H; or lower alkyl; R64: alkyl; alkenyl; aryl; and aryl-lower alkyl; heteroaryl-lower alkyl);
-(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; or lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -
(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -
(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or -(CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy). - R6: H; lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55: lower alkyl; or lower alkenyl); -
(CH2)0SR56 (where R56 : lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2---; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl);
-(CH2)00C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0NR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl);
-(CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; or lower alkyl; or R58 and
R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where
R60 : lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)qC6H-|R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R7: lower alkyl; lower alkenyl; -(CH2)qOR55 (where R55 : lower alkyl; or lower alkenyl); -
(CH2)qSR56 (where R56 : lower alkyl; or lower alkenyl); -(CH2)qNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)q0C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); (CH2)qNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)qN(R20)COR64(where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)rCOOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)qCONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; or lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)rPO(OR60)2 (where R60 : lower alkyl; or lower alkenyl); (CH2)rS02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl;or lower alkoxy). - Rs: H; F; Cl; CF3; lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55: lower alkyl; or lower alkenyl); (CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; - (CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); - (CH2)0OCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl);
-(CH2)oNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl);
-(CH2)0COOR57 (where R57 : lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 : lower alkyl; or lower alkenyl; and R59: H; or lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0PO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or -(CH2)qC6R,R8 (where R8: H; F; Cl; CF ; lower alkyl; lower alkenyl; or lower alkoxy).
R9: lower alkyl; lower alkenyl; -(CH2)00R55 (where R55: lower alkyl; or lower alkenyl); - (CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)00C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H, or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H, or lower alkyl); -(CH2)oN(R20)COR64(where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 : lower alkyl; or lower alkenyl; and R59: H; or lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R'°: lower alkyl; lower alkenyl; -(CH2)00R55 (where R55: lower alkyl; or lower alkenyl); - (CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)M-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)00C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)M-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oN(R20)COR64(where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COORS7 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)QS02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)qC6H R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R": H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)mSR56 (where R55: lower alkyl; or lower alkenyl); -(CH2)mNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2- ; -(CH2)2S(CH2)2-; or -(CH2)2NRS7(CH2)2-; where R57: H; or lower alkyl); -(CH2)m0C0NR33R75
(where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: - (CH, ; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0C00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy). R12: H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)mSR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)mNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2- ; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75taken together form: - (CH. ; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)rCOOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)rCONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; or lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)rPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
Ru: lower alkyl; lower alkenyl; -(CH2)q0R55 (where R55: lower alkyl; or lower alkenyl); - (CH2)qSR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)qNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)q0C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)qNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)qN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)rC0057 (where R57: lower alkyl; or lower alkenyl); - (CH2)qCONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; or lower alkyl;or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)-PO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)rS02R62 (where R62: lower alkyl; or lower alkenyl); or -(CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R14: H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)mSR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)mNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2- ; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)m0C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: - (CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20: H; lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); - (CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; or lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0PO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); - (CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R,5\ lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0OCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where RS7: H; or lower alkyl); (CH2)oN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); particularly favoured are NR20COlower alkyl (R20=H; or lower alkyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl);
-(CH2)0CONR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60 : lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or -(CH2)q H-tR8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R16: lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2.6-; -(CH2)2θ(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oN(R20)COR64 (where R20 H, or lower alkyl, R64 lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 lower alkyl, or lower alkenyl, and R59 H, or lower alkyl, or R58 and R59 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oPO(OR60)2 (where R60 lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 lower alkyl, or lower alkenyl), or - (CH2)qC6H4R8 (where R8 H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy)
R17 lower alkyl, lower alkenyl, -(CH2)qOR55 (where R55 lower alkyl, or lower alkenyl), - (CH2)qSR56 (where R56 lower alkyl, or lower alkenyl), -(CH2)qNR33R34 (where R33 lower alkyl, or lower alkenyl, R34 H, or lower alkyl, or R33 and R34 taken together form
-(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)q0C0NR33R75 (where R33 H, or lower alkyl, or lower alkenyl, R7S lower alkyl, or R33 and R75 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)qNR20CONR33R82 (where R20 H, or lower lower alkyl, R33 H, or lower alkyl, or lower alkenyl, R82 H, or lower alkyl, or R33 and R82 taken together form -(CH2)2.6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or
-(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)qN(R20)COR6 (where R20 H, or lower alkyl, R64 lower alkyl, or lower alkenyl), -(CH2)rCOOR57 (where R57 lower alkyl, or lower alkenyl), -(CH2)qCONR58R59 (where R58 lower alkyl, or lower alkenyl, and R59 H, lower alkyl, or R58 and R59 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-,
-(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)rPO(OR60)2 (where R60 lower alkyl, or lower alkenyl), -(CH2)rS02R62 (where R62 lower alkyl, or lower alkenyl), or - (CH2)qC6H4R8 (where R8 H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy)
Among the building blocks Al to A69 the following are preferred A5 with R2 being H, A8, A22, A25, A38 with R2 being H, A42, A47, and A50 Most preferred are building blocks of type A8'
A8" wherein R20 is H or lower alkyl, and R64 is alkyl, alkenyl, aryl, aryl-lower alkyl, or heteroaryl-lower alkyl, especially those wherein R64 is n-hexyl (A8'-l), n-heptyl (A8'-2), 4-(phenyl)benzyl (A8'-3), diphenylmethyl (A8'-4), 3-ammo-propyl (A8'-5), 5-amιno-pentyl (A8'-6), methyl (A8'-7), ethyl (A8'-8), isopropyl (A8'-9), isobutyl (A8'-10), n-propyl (A8'-ll), cyclohexyl (A8*-12), cyclohexylmethyl (A8'-13), n-butyl (A8'-14), phenyl (A8'-15), benzyl (A8'-16), (3-ιndolyl)methyl (A8'-17), 2-(3-ιndolyl)ethyl (A8'-18), (4-phenyl)phenyl (A8'-19), and n-nonyl (A8'-20)
Building block A70 belongs to the class of open-chained α-substituted α-amino acids, building blocks A71 and A72 to the corresponding β-amino acid analogues and building blocks A73-A104 to the cyclic analogues of A70 Such amino acid derivatives have been shown to constrain small peptides in well defined reverse turn or U-shaped conformations (C M Venkatachalam, Biopolymers, 1968, 6, 1425-1434, W Kabsch, C Sander, Biopolymers 1983, 22, 2577) Such building blocks or templates are ideally suited for the stabilization of β-hairpin conformations in peptide loops (D Obrecht, M Altorfer, J A Robinson, "Novel Peptide Mimetic Building Blocks and Strategies for Efficient Lead Finding", Adv Med Chem 1999, Vol 4, 1-68, P Balaram, "Non-standard amino acids in peptide design and protein engineering", Curr Opin Struct Biol 1992, 2, 845-851, M Cπsma, G Valle, C Toniolo, S Prasad, R B Rao, P Balaram, "β-turn conformations m crystal structures of model peptides containing α,α- disubstituted amino acids", Biopolymers 1995, 35, 1 -9, V J Hruby, F Al-Obeιdι, W Kazmierski, Biochem J 1990, 268, 249-262)
It has been shown that both enantiomers of building blocks -A70-CO- to A104-CO- in combination with a building block -B-CO- of L-configuration can efficiently stabilize and induce β-hairpin conformations (D Obrecht, M Altorfer, J A Robinson, "Novel Peptide Mimetic Building Blocks and Strategies for Efficient Lead Finding", Adv Med Chem 1999, Vol 4, 1 -68, D Obrecht, C
Spiegler, P Schonholzer, K Muller, H Heimgartner, F Stιerh, He/v Chim Acta 1992, 75, 1666- 1696, D Obrecht, U Bohdal, J Daly, C Lehmann, P Schonholzer, K Muller, Tetrahedron 1995, 57, 10883-10900, D Obrecht, C Lehmann, C Ruffieux, P Schonholzer, K Muller, Helv Chim Acta 1995, 78, 1567-1587, D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 563-580, D Obrecht, Η Karajianms, C Lehmann, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 75, 703-714)
Thus, for the purposes of the present invention templates (al) can also consist of -A70-CO- to A104- CO- where building block A70 to A104 is of either (D)- or (L)-configuratιon, in combination with a building block -B-CO- of (L)- configuration
Preferred values for R20 in A70 to A104 are Η or lower alkyl with methyl being most preferred Preferred values for R18, R19 and R21-R29 in building blocks A70 to A104 are the following R'8 lower alkyl - R'9 lower alkyl, lower alkenyl, -(CΗ2)pOR55 (where R55 lower alkyl, or lower alkenyl), -
(CH2)PSR56 (where R56 lower alkyl, or lower alkenyl), -(CH2)PNR33R34 (where R33 lower alkyl, or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)pOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)pNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)PN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)PC00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)PC0NR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; or lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)PS02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)0C6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy). - R2': H; lower alkyl; lower alkenyl; -(CH2)00R55 (where R55: lower alkyl; or lower alkenyl); -
(CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NRS7(CH2)2-; where R57: H; or lower alkyl); -(CH2)0OCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R7S: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0C00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0C0NR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CHJ^NR^CHJ ; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); (CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or (CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R": lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0OCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75; lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where RS7: H; or lower alkyl); -(CH2)oN(R20)COR64(where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where RS7: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where
R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or -
(CH2)qC6H4R8 (where R8: H; F; Cl; CF; lower alkyl; lower alkenyl; or lower alkoxy). - R23: H; lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55: lower alkyl; or lower alkenyl); -
(CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl);
-(CH2)00C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); particularly favoured are NR20COlower alkyl (R20=H; or lower alkyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl);
-(CH2)0CONR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or
-(CH2)qC6HtR8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy);
R24: lower alkyl; lower alkenyl; -(CH2)00R55 (where R55: lower alkyl; or lower alkenyl); -
(CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl);
-(CH2)00C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); particularly favoured are NR20COlower alkyl (R20=H ; or lower alkyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl);
-(CH2)0CONR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0SO2R62 (where R62: lower alkyl; or lower alkenyl); or
-(CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy);
R25: H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)mNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2_6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)m0C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2-«-; - (CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)nιNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2_6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)„,N(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0C00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0C0NR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or -(CH2)qC6H R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R26: H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)mNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mN(R20)COR64(where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0C00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0C0NR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or -(CH^ I^R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
Alternatively, R25 and R26 taken together can be -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl). - R27: H; lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55: lower alkyl; or lower alkenyl); -
(CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)o0C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0NR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R2S : lower alkyl; lower alkenyl; -(CH2)00R55 (where R55: lower alkyl; or lower alkenyl); - (CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)00C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R7S: lower alkyl; or R33 and R75 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0NR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oN(R20)COR6 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0C00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0C0NR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy). R29 lower alkyl, lower alkenyl, -(CH2)0OR55 (where R55 lower alkyl, or lower alkenyl), -
(CH2)0SR56 (where R56 lower alkyl, or lower alkenyl), -(CH2)0NR33R34 (where R33 lower alkyl, or lower alkenyl, R34 H, or lower alkyl, or R33 and R34 taken together form
-(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)0OCONR33R75 (where R33 H, or lower alkyl, or lower alkenyl, R75 lower alkyl, or R33 and R75 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or
-(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oNR20CONR33R82 (where R20 H, or lower lower alkyl, R33 H, or lower alkyl, or lower alkenyl, R82 H, or lower alkyl, or R33 and R82 taken together form -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oN(R20)COR6 (where R20 H, or lower alkyl, R64 lower alkyl, or lower alkenyl), particularly favored are NR20COlower-alkyl (R20=H, or lower alkyl), -(CH2)0COOR57 (where R57 lower alkyl, or lower alkenyl),
-(CH2)0CONR58R59 (where R58 lower alkyl, or lower alkenyl, and R59 H, lower alkyl, or R58 and R59 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oPO(OR60)2 (where R60 lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 lower alkyl, or lower alkenyl), or
-(CH?)qC6H4R8 (where R8 H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy)
For templates (b) to (p), such as (bl) and (cl), the preferred values for the various symbols are the following
Rs H, F, Cl, CF3, lower alkyl, lower alkenyl, -(CH2)0OR55 (where R55 lower alkyl, or lower alkenyl), -(CH2)0SR56 (where R56 lower alkyl, or lower alkenyl), -(CH2)0NR33R34 (where R33 lower alkyl, or lower alkenyl, R34 H, or lower alkyl, or R33 and R34 taken together form -(CH2)2 6-, - (CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), - (CH2)0OCONR33R75 (where R33 H, or lower alkyl, or lower alkenyl, R75 lower alkyl, or R33 and R75 taken together fonn -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl),
-(CH2)0NR20CONR33R82 (where R20 H, or lower lower alkyl, R33 H, or lower alkyl, or lower alkenyl, R82 H, or lower alkyl, or R33 and R82 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oN(R20)COR64 (where R20 H, or lower alkyl, R64 lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 lower alkyl, or lower alkenyl, and R59 H, or lower alkyl, or R58 and R59 taken together form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 H, or lower alkyl), -(CH2)oPO(OR60)2 (where R60 lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 lower alkyl, or lower alkenyl), or -(CH^- I^R8 (where R8 H, F, Cl, CF , lower alkyl, lower alkenyl, or lower alkoxy) R20: H; or lower alkyl. R30: H, methyl.
R31: H; lower alkyl; lower alkenyl; -(CH2)P0R55 (where R55: lower alkyl; or lower alkenyl); - (CH2)PNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)POCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2) -6-; - (CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)PNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)PN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)„COOR57 (where R57: lower alkyl; or lower alkenyl); (-CH2)0CONR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0PO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or -(CH2)rC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy); most preferred is -CH2C0NR58R59 (R58: H; or lower alkyl; R59: lower alkyl; or lower alkenyl). - R32: H, methyl.
R33: lower alkyl; lower alkenyl; -(CH2)m0R55 (where R55: lower alkyl; or lower alkenyl); - (CH2)mNR34R63 (where R34: lower alkyl; or lower alkenyl; R63: H; or lower alkyl; or R34 and R63 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl) ; (CH2)m0C0NR75R82(where R75: lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R75 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2- ; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl);
-(CH2)mNR20CONR78R82 (where R20: H; or lower lower alkyl; R78: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R78 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl);
-(CH2)0C00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0C0NR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or RS8 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl). R34: H; or lower alkyl. - R35: H; lower alkyl; lower alkenyl; -(CH2)m0R55 (where R55: lower alkyl; or lower alkenyl); -
(CH2)mNR33R34 (Where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)„,N(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0C00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)oC0NR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl). R36: lower alkyl; lower alkenyl; or aryl-lower alkyl.
R37: H; lower alkyl; lower alkenyl; -(CH2)pOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)pNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)p0C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2-δ-; - (CH2)2θ(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)pNR20CONR33R82 (where R20: H; or lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)pN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 : lower alkyl; or lower alkenyl); -(CH2)0CONRS8R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alky; or lower alkenyl); or -(CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R3S: H; lower alkyl; lower alkenyl; -(CH2)P0R55 (where R55: lower alkyl; or lower alkenyl); - (CH2)PNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)p0C0NR3 R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R78 taken together form: -(CH2)2-6-; - (CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)PNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)PN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)oC0NR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and RS9 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or -(CH2)qC6H-,R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R39: H; lower alkyl; lower alkenyl; -(CH2)mOR5S (where RS5: lower alkyl; or lower alkenyl); - (CH2)n.N(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); - (CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2) .6-; - (CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl). R40: lower alkyl; lower alkenyl; or aryl-lower alkyl.
R4': H; lower alkyl; lower alkenyl; -(CH2)P0R55 (where R55: lower alkyl; or lower alkenyl); - (CH2)PNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)P0C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)PNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)PN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0C00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0C0NR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alky; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or -(CH2)qC6HjR8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R42: H; lower alkyl; lower alkenyl; -(CH2)P0R55 (where R55: lower alkyl; or lower alkenyl); - (CH2)PNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2_6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)p0C0NR3 R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH )2~--; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)pNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)PN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl, or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R43: H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)mSR56 (where R56 : lower alkyl; or lower alkenyl); -(CH2)mNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R7S taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)0PO(OR60)2 (where R60: lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62: lower alkyl; or lower alkenyl); or - (CH2)qC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R44: lower alkyl; lower alkenyl; -(CH2)pOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)PSR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)PNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)p0C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R78 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where RS7: H; or lower alkyl); -(CH2)PNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)PN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)PC00R57 (where R57: lower alkyl; or lower alkenyl); -(CH2)pC0NR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2) -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); or -(CH2)0C6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R45: H; lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)0SR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)sOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together fonn: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)oN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); or -(CH2)bC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R46: H; lower alkyl; lower alkenyl; -(CH2)sOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)SSR56 (where R56: lower alkyl; or lower alkenyl); -(CH2)SNR3 R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form:
-(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)sOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)SNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH,)2-; where R57: H; or lower alkyl); -(CH2)bN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together fonn: -(CH2)2.6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); or -(CH2)S ,H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R47: H; or OR55 (where R55: lower alkyl; or lower alkenyl).
R" H; or lower alkyl.
R 49 H;lower alkyl; -(CH2)0COOR57 (where R57 : lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); or (CH2)SC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy). R50: H; methyl.
R5': H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)mNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); (CH2)mOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)pCOOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)pCONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59 : H; lower alkyl; or R58 and R59 taken together form:
-(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); or -(CH2)rC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R52: H; lower alkyl; lower alkenyl; -(CH )mOR55 (where R55: lower alkyl; or lower alkenyl); - (CH2)mNR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mOCONR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2) .6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; R57: H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)pCOOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)pCONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); or -(CH2)rC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
R53: H; lower alkyl; lower alkenyl; -(CH2)m0R55 (where R55: lower alkyl; or lower alkenyl); - (CH2),„NR33R34 (where R33: lower alkyl; or lower alkenyl; R34: H; or lower alkyl; or R33 and R34 taken together form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)„,0C0NR33R75 (where R33: H; or lower alkyl; or lower alkenyl; R75: lower alkyl; or R33 and R75 taken together form: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20: H; or lower lower alkyl; R33: H; or lower alkyl; or lower alkenyl; R82: H; or lower alkyl; or R33 and R82 taken together form: -(CH2)2-e-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20: H; or lower alkyl; R64: lower alkyl; or lower alkenyl); -(CH2)pCOOR57 (where R57: lower alkyl; or lower alkenyl); -(CH2)pCONR58R59 (where R58: lower alkyl; or lower alkenyl; and R59: H; lower alkyl; or R58 and R59 taken together form: -(CHJ ; -(CH2)2θ(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); or -(CH2)rC6H4R8 (where R8: H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy). R54: lower alkyl; lower alkenyl; or aryl-lower alkyl.
Among the building blocks A70 to A104 the following are preferred: A74 with R22 being H, A75, A76, A77 with R22 being H, A78 and A79.
The building block -B-CO- within template (al) and (a2) designates an L-amino acid residue. Preferred values for B are: -NR20CH(R71)- and enantiomers of groups A5 with R2 being H, A8, A22, A25, A38 with R2 being H, A42, A47, and A50. Most preferred are Ala L-Alanine
Arg L-Arginine
Asn L-Asparagine
Cys L-Cysteine Gin L-Glutamine
Gly Glycine
His L-Histidine
He L-Isoleucine
Leu L-Leucine Lys L-Lysine
Met L-Methionine
Phe L-Phenylalanine
Pro L-Proline
Ser L-Serine Thr L-Threonine
Trp L-Tryptophan
Tyr L-Tyrosine
Val L-Valine
Cit L-Citrulline Om L-Ornithine tBuA L-t-Butylalanine
Sar Sarcosine t-BuG L-tert -Butylglycine
4AmPhe L-para-Ammophenylalanine
3AmPhe L-meta-Aminophenylalanine
2AmPhe L-ortho-Aminophenylalanine
Phe(mC(NH2)=NH) L-meta-Amidinophenylalamne
Phe(pC(NH2)=NH) L-para-Amidinophenylalanine
Phe(mNHC (NH2)=NH) L-meta-Guanidinophenylalamne
Phe(pNHC (NH2)=NH) L-para-Guanidmophenylalanine
Phg L-Phenylglycine
Cha L-Cyclohexylalanine
C4al L-3 -Cy clobutylalanine
C5al L-3-Cyclopentylalamne
Nle L-Norleucme
2-Nal L-2-Naphthylalamne
1-Nal L- 1 -Naphthylalanine
4C1-Phe L-4-Chlorophenylalanιne
3C1-Phe L-3 -Chlorophenylalanine
2C1-Phe L-2-Chlorophenylalanιne
3,4C12 Phe L-3,4-Dιchlorophenylalanιne
4F-Phe L-4-Fluorophenylalanιne
3F-Phe L-3 -Fluorophenylalanme
2F-Phe L-2-Fluorophenylalanιne
Tic L-l,2,3,4-Tetrahydroιsoquιnohne-3- -carboxylic acid
Thi L-β-2-Thιenylalanme
Tza L-2 -Thiazolylalanine
Mso L-Methionme sulfoxide
AcLys L-N-Acetyllysine
Dpr L-2,3-Dιamιnopropιonιc acid
A2Bu L-2,4-Dιamιnobutyπc acid
Dbu (S)-2,3-Dιamιnobutyπc acid
Abu γ-Aminobutyπc acid (GABA)
Aha ε-Aminohexanoic acid
Aib α-Aminoisobutyπc acid
Y(Bzl) L-O-Benzyltyrosine
Bip L-Biphenylalanine
S(Bzl) L-O-Benzylseπne T(Bzl) L-O-Benzylthreonine hCha L-Homo-cyclohexylalamne hCys L-Homo-cysteme hSer L-Homo-seπne hArg L-Homo-arginine hPhe L-Homo-phenylalanme
Bpa L-4-Benzoylphenylalanme
Pip L-Pipecohc acid
OctG L-Octylglycine
MePhe L-N-Methylphenylalanme
MeNle L-N-Methylnorleucine
MeAla L-N-Methylalanme
Melle L-N-Methylisoleucme
MeVal L-N-Methvahne
MeLeu L-N-Methylleucine
In addition, the most preferred values for B also include groups of type A8" of (L)-confιguratιon
A8" wherein R20 is H or lower alkyl and R64 is alkyl, alkenyl, aryl, aryl-lower alkyl, or heteroaryl-lower alkyl, especially those wherein R64 is n-hexyl (A8"-21), n-heptyl (A8"-22), 4-(phenyl)benzyl (A8"- 23), diphenylmethyl (A8"-24), 3-amιno-propyl (A8"-25), 5-amιno-pentyl (A8"-26), methyl (A8M- 27), ethyl (A8"-28), isopropyl (A8"-29), isobutyl (A8"-30), n-propyl (A8"-31), cyclohexyl (A8"- 32), cyclohexylmethyl (A8"-33), n-butyl (A8"-34), phenyl (A8"-35), benzyl (A8"-36), (3- ιndolyl)methyl (A8"-37), 2-(3-ιndolyl)ethyl (A8"-38), (4-phenyl)phenyl (A8"-39), and n-nonyl (A8"-40)
The peptidic chain Z of the β-hai in mimetics described herein is generally defined in terms of amino acid residues belonging to one of the following groups
Group C -NR20CH(R72)CO-, "hydrophobic small to medium-sized" Group D -NR20CH(R73)CO-, "hydrophobic large aromatic or heteroaromatic" Group E -NR20CH(R74)CO-, "polar-cationic" and "urea-deπved" Group F -NR20CH(R84)CO-, "polar-non-charged" Group H -NR20-CH(CO-)-(CH2)4 7-CH(CO-)-NR20-,
-NR20-CH(CO-)-(CH2)pSS(CH2)p-CH(CO-)-NR20-, -NR20-CH(CO-)-(-(CH2)pNR20CO(CH2)p-CH(CO-)-NR20-, and -NR20-CH(CO-)-(-(CH2)pNR20CONR20(CH2)p-CH(CO-)-NR20-,
"interstrand linkage" Furthermore, the amino acid residues m chain Z can also be of formula -A-CO- or of formula -B-CO- wherein A and B are as defined above Finally, Gly can also be an amino acid residue in chain Z, and Pro can be an ammo acid residue in chain Z, too, with the exception of positions where interstrand linkages (H) are possible
Group C comprises amino acid residues with small to medium-sized hydrophobic side chain groups according to the general definition for substituent R72 A hydrophobic residue refers to an amino acid side chain that is uncharged at physiological pH and that is repelled by aqueous solution Furthermore these side chains generally do not contain hydrogen bond donor groups, such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas However, they may contain hydrogen bond acceptor groups such as ethers, thioethers, esters, tertiary amides, alkyl- or aryl phosphonates and phosphates or tertiary amines Genetically encoded small-to-medium-sized amino acids include alanine, isoleucine, leucine, methionine and valine
Group D comprises ammo acid residues with aromatic and heteroaromatic side chain groups according to the general definition for substituent R73 An aromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated π- electron system (aromatic group) In addition they may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, ternary amides, alkyl- or aryl phosphonates -and phosphates or tertiary amines Genetically encoded aromatic amino acids include phenylalanine and tyrosine
A heteroaromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated π-system incorporating at least one heteroatom such as (but not limited to) O, S and N according to the general definition for substituent R77 In addition such residues may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, ternary amides, alkyl- or aryl phosphonates - and phosphates or tertiary amines Genetically encoded heteroaromatic amino acids include tryptophan and histidine
Group E comprises amino acids containing side chains with polar-cationic, acylamino- and urea- derived residues according to the general definition for substituen R Polar-cationic refers to a basic side chain which is protonated at physiological pH Genetically encoded polar-cationic ammo acids include arginine, lysine and histidine Citrulhne is an example for an urea derived amino acid residue
Group F comprises ammo acids containing side chains with polar-non-charged residues according to the general definition for substituent R84 A polar-non-charged residue refers to a hydrophilic side chain that is uncharged at physiological pH, but that is not repelled by aqueous solutions Such side chains typically contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas These groups can form hydrogen bond networks with water molecules In addition they may also contain hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetπary amides, alkyl- or aryl phosphonates -and phosphates or tertiary amines Genetically encoded polar-non-charged amino acids include asparagme, cysteine, glutamine, serine and threonine
Group H comprises side chains of preferably (L)-amιno acids at opposite positions of the β-strand region that can form an interstrand linkage The most widely known linkage is the disulfide bridge formed by cystemes and homo-cysteines positioned at opposite positions of the β-strand Various methods are known to form disulfide linkages including those described by J P Tam et al Synthesis 1979, 955-957, Stewart et al , Solid Phase Peptide Synthesis, 2d Ed , Pierce Chemical Company, III , 1984, Ahmed et al J Biol Chem 1975, 250, 8477-8482 , and Pennington et al , Peptides, pages 164- 166, Giralt and Andreu, Eds , ESCOM Leiden, The Netherlands, 1990 Most advantageously, for the scope of the present invention, disulfide linkages can be prepared using acetamidomethyl ( Acm)- protective groups for cysteine A well established interstrand linkage consists in linking ornithines and lysmes, respectively, with glutamic and aspartic acid residues located at opposite β-strand positions by means of an amide bond formation Prefened protective groups for the side chain amino- groups of ornithine and lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic and glutamic acid Finally, interstrand linkages can also be established by linking the amino groups of lysine and ornithine located at opposite β-strand positions with reagents such as N,N-carbonyhmιdazole to form cyclic ureas As mentioned earlier, positions for interstrand linkages are positions P4 and P9, and/or P2 and PI 1 taken together Such interstrand linkages are known to stabilize the β-hairpm conformations and thus constitute an important structural element for the design of β-hairpin mimetics
Most prefened ammo acid residues in chain Z are those derived from natural α-ammo acids
Hereinafter follows a list of ammo acids which, or the residues of which, are suitable for the purposes of the present invention, the abbreviations conespond g to generally adopted usual practice
three letter code one letter code
Ala L-Alanine A
Arg L-Argimne R
Asn L-Asparagine N
Asp L-Aspartic acid D
Cys L-Cysteine C
Glu L-Glutamic acid E
Gin L-Glutamine Q
Gly Glycine G
His L-Histidine H
He L-Isoleucine I
Leu L-Leucine L
Lys L-Lysine K
Met L-Methionine M
Phe L-Phenylalanme F
Pro L-Prohne P
DPro D-Prohne Dp
Ser L-Seπne S
Thr L-Threonine T
Trp L-Tryptophan W
Tyr L-Tyrosine Y
Val L-Vahne V
Other α-amino acids which, or the residues of which, are suitable for the purposes of the present invention include
Cit L-Citrulhne Orn L-Ornithine tBuA L-t-Butylalanine
Sar Sarcosine
Pen L-Penicillamine t-BuG L-tert -Butylglycine
4AmPhe L-para-Aminophenylalanine
3AmPhe L-meta-Aminophenylalanine
2AmPhe L-ortho-Aminophenylalanine
Phe(mC(NH2)=NH) L-meta-Amidinophenylalanine Phe(pC(NH2)=NH) L-para-Amidinophenylalanine
Phe(mNHC (NH2)=NH) L-meta-Guanidinophenylalanine Phe(pNHC (NH2)=NH) L-para-Guanidmophenylalanine
Phg L-Phenylglycme
Cha L-Cyclohexylalanine C al L-3-Cyclobutylalanιne
C5al L-3-Cyclopentylalanιne
Nle L-Norleucme
2-Nal L-2-Naphthylalanιne
1 -Nal L- 1 -Naphthylalanme 4C1-Phe L-4-Chlorophenylalanme
3C1-Phe L-3-Chlorophenylalanιne
2C1-Phe L-2-Chlorophenylalanιne
3 ,4C12-Phe L-3 ,4-Dιchlorophenylalanιne
4F-Phe L-4-Fluorophenylalanιne 3F-Phe L-3-Fluorophenylalanιne
2F-Phe L-2-Fluorophenylalanιne
Tic l,2,3,4-Tetrahydroιsoquιnohne-3-carboxylιc acid
Thi L-β-2-Thιenylalanιne
Tza L-2-Thιazolylalanιne Mso L-Methionme sulfoxide
AcLys N-Acetyllysme
Dpr 2,3-Dιamιnopropιonιc acid
A2Bu 2,4-Dιammobutync acid
Dbu (S)-2,3-Dιamιnobutyrιc acid Abu γ-Aminobutyπc acid (GAB A)
Aha ε-Aminohexanoic acid
Aib α-Aminoisobutyπc acid 53
Y(Bzl) L-O-Benzyltyrosine
Bip L-(4-phenyl)phenylalanιne
S(Bzl) L-O-Benzylseπne
T(Bzl) L-O-Benzylthreonme hCha L-Homo-cyclohexylalamne hCys L-Homo-cysteine hSer L-Homo-seπne hArg L-Homo-argmine hPhe L-Homo-phenylalanine
Bpa L-4-Benzoylphenylalanιne
4-AmPynl (2S ,4S)-4-Amιno-pyrrolιdιne-L-carboxylιc acid
4-AmPyrr2 (2S,4R)-4-Amιno-pyrrohdιne-L-carboxyhc acid
4-PhePynl (2S,5R)-4-Phenyl-pyrrohdιne-L-carboxylιc acid
4-PhePyn2 (2S,5S)-4-Phenyl-pyrrohdιne-L-carboxylιc acid
5-PhePyrrl (2S,5R)-5-Phenyl-pyrrohdιne-L-carboxyhc acid
5-PhePyn2 (2S,5S)-5-Phenyl-pyrrolιdιne-L-carboxylιc acid
Pro(4-OH)l (4S)-L-Hydroxyprolιne
Pro(4-OH)2 (4R)-L-Hydroxyprohne
Pip L-Pipecohc acid
DPιp D-Pipecohc acid
OctG L-Octylglycine
MePhe L-N-Methylphenylalanine
MeNl'e L-N-Methylnorleucine
MeAla L-N-Methylalanme
Melle L-N-Methyhsoleucine
MeVal L-N-Methylvahne
MeLeu L-N-Methylleucine
Particularly preferred residues for group C are Ala L-Alanine
He L-Isoleucine
Leu L-Leucine
Met L-Methionine
Val L-Vahne tBuA L-t-Butylalanine t-BuG L-tert -Butylglycine
Cha L-Cyclohexylalanine C4al L-3-Cyclobutylalanιne
C5al L-3-Cyclopentylalanιne
Nle L-Norleucine hCha L-Homo-cyclohexylalanine OctG L-Octylglycine
MePhe L-N-Methylphenylalanine
MeNle L-N-Methylnorleucine
MeAla L-N-Methylalanme
Melle L-N-Methyhsoleucine MeVal L-N-Methylvahne
MeLeu L-N-Methylleucine
Particularly prefened residues for group D are
His L-Histidine Phe L-Phenylalanine
Trp L-Tryptophan
Tyr L-Tyrosine
Phg L-Phenylglycine
2-Nal L-2-Naphthylalanιne 1-Nal L-1-Naphthylalanιne
4C1-Phe L-4-Chlorophenylalanιne
3C1-Phe L-3-Chlorophenylalanιne
2C1-Phe L-2-Chlorophenylalanιne
3,4C12-Phe L-3,4-Dιchlorophenylalanιne 4F-Phe L-4-Fluorophenylalanιne
3F-Phe L-3-Fluorophenylalanme
2F-Phe L-2-Fluorophenylalanιne
Thi L-β-2-Thιenylalanιne
Tza L-2-Thιazolylalanιne Y(Bzl) L-O-Benzyltyrosine
Bip L-Biphenylalanine
S(Bzl) L-O-Benzylseπne
T(Bzl) L-O-Benzylthreonme hPhe L-Homo-phenylalanine Bpa L-4-Benzoylphenylalanιne
Particularly prefened residues for group E are Arg L-Argimne
Lys L-Lysine
Orn L-Ornithine
Dpr L-2,3-Dιamιnopropιonιc acid
A2Bu L-2,4-Dιamιnobutyπc acid
Dbu (S)-2,3-Dιamιnobutyrιc acid
Phe(pNH2) L-para-Aminophenylalanine
Phe(mNH2) L-meta-Aminophenylalanme
Phe(oNH2) L-ortho-Aminophenylalamne hArg L-Homo-arginme
Phe(mC(NH2)=NH) L-meta-Amidmophenylalanme
Phe(pC(NH2)=NH) L-para-Amidinophenylalanine
Phe(mNHC (NH2)=NH) L-meta-Guanidinophenylalanine
Phe(pNHC (NH2)=NH) L-para-Guanidinophenylalamne
Cit L-Citrulhne
Particularly preferred residues for group F are
Asn L-Asparagine Cys L-Cysteine
Gin L-Glutamine
Ser L-Seπne
Thr L-Threonine
Cit L-Citrulhne Pen L-Penicillamine
AcLys L-Nε-Acetyllysιne hCys L-Homo-cysteine hSer L-Homo-seπne
Generally, the peptidic chain Z within the β-hairpin mimetics of the invention comprises 12 amino acid residues The positions PI to PI 2 of each am o acid residue in the chain Zare unequivocally defined as follows PI represents the first amino acid in the chain Z that is coupled with its N- terminus to the C-termmus of the templates (b)-(p) or of group -B-CO- in template (al), or of group - A-CO- in template a2, and P12 represents the last am o acid m the chain Z that is coupled with its C-terminus to the N-terminus of the templates (b)-(p) or of group -A-CO- in template (al) or of group -B-CO- in template (a2) Each of the positions PI to PI 2 will preferably contain an amino acid residue belonging to one of the above types C to F, or of fomiula -A-CO- or of formula -B-CO- as follows
PI of type C or of type D or of type E or of type F, P2 of type D, - P3 of type C,
P4 of type E, or of type C, P5 of type E, or of type F, P6 of type E, or of type F, or of formula -A-CO-, P7 of type E, or of type F, or of fomiula -B-CO-, - P8 of type D, or of type C, or of Type F,
P9 of type C, or of type E, P10 of type F, or of type D, or of type C, Pl l of type D, or of type C, or of type F, P12 of type C or of type D or of type E or of type F, at P6 and P7 also D-isomers being possible, with the proviso that the amino acid residue in position P4 is of type C, and/or the amino acid residue in position P5 is of type F, and/or the amino acid residue in position P8 is of type F, and/or - the amino acid residue in position P9 is of type C, and/or the ammo acid residue in position P10 is of type F, and/or the amino acid residue in position PI 1 is of type C or F
Most preferably, the amino acid residues in positions PI to P12 are - PI Arg,
P2 Trp,
P3 Leu,
P4 Lys or Val,
P5 Lys, - P6 Arg,
P7 Arg,
P8 Trp,
P9 Leu, Val or Lys,
P10 Tyr, Thr or Gin, - Pl l Val, Leu, Tyr or Gin, and
PI 2 Arg, with the proviso that the amino acid residue in position P4 is Val, and/or the amino acid residue in position P9 is Leu or Val, and/or the amino acid residue in position P10 is Thr or Gin, and/or the amino acid residue in position PI 1 is Val or Leu or Gin
Particularly prefened β-peptidomimetics of the invention include those described in Examples 1 , to 8
The processes of the invention can advantageously be carried out as parallel array syntheses to yield libraries of template-fixed β-hairpin peptidomimetics of the above general formula I Such parallel syntheses allow one to obtain anays of numerous (normally 24 to 192, typically 96) compounds of general formula I in high yields and defined purities, minimizing the formation of dimeric and polymeric by-products The proper choice of the functionalized solid-support (I e solid support plus linker molecule), templates and site of cyclization play thereby key roles
The functionalized solid support is conveniently derived from polystyrene crosshnked with, preferably 1-5%, divinylbenzene, polystyrene coated with polyethyleneglycol spacers (TentagelR), and polyacrylamide resins (see also Obrecht, D , Villalgordo, J -M, "Solid- Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries", Tetrahedron Organic Chemistry Series, Vol 17, Pergamon, Elsevier Science, 1998)
The solid support is functionalized by means of a linker, l e a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures For the purposes of the present invention the linker must be designed to eventually release the carboxyl group under mild acidic conditions which do not affect protecting groups present on any functional group in the side-chains of the various amino acids Linkers which are suitable for the purposes of the present invention form acid-labile esters with the carboxyl group of the amino acids, usually acid-labile benzyl, benzhydryl and tπtyl esters, examples of linker structures of this kind include 2-methoxy-4-hydroxymethylphenoxy (SasπnR linker), 4-(2,4-dιmethoxyphenyl- hydroxymethyl)-phenoxy (Rink linker), 4-(4-hydroxymethyl-3-methoxyphenoxy)butyπc acid (HMPB linker), tπtyl and 2-chlorotntyl
Preferably, the support is derived from polystyrene crosshnked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 2-chlorotntyl linker When earned out as a parallel array syntheses the processes of the invention can be advantageously earned out as described herein below but it will be immediately apparent to those skilled in the art how these procedures will have to be modified in case it is desired to synthesize one single compound of the above formula I
A number of reaction vessels (normally 24 to 192, typically 96) equal to the total number of compounds to be synthesized by the parallel method are loaded with 25 to 1000 mg, preferably 100 mg, of the appropriate functionalized solid support, preferably 1 to 3% cross linked polystyrene or tentagel resin
The solvent to be used must be capable of swelling the resin and includes, but is not limited to, dichloromethane (DCM), dimethylformamide (DMF), N-methylpyrrohdone (NMP), dioxane, toluene, tetrahydrofuran (THF), ethanol (EtOH), tnfluoroethanol (TFE), isopropylalcohol and the like Solvent mixtures containing as at least one component a polar solvent (e g 20% TFE/DCM, 35% THF/NMP) are beneficial for ensuring high reactivity and solvation of the resm-bound peptide chains ( Fields, G B , Fields, C G , J - m Chem Soc 1991, 773, 4202-4207)
With the development of various linkers that release the C-terminal carboxylic acid group under mild acidic conditions, not affecting acid-labile groups protecting functional groups in the side chaιn(s), considerable progresses have been made in the synthesis of protected peptide fragments The 2- methoxy-4-hydroxybenzylalcohol-deπved linker (SasπnR linker, Mergler et al , Tetrahedron Lett 1988, 294005-4008) is cleavable with diluted tnfluoroacetic acid (0 5-1% TFA in DCM) and is stable to Fmoc deprotection conditions during the peptide synthesis, Boc/tBu-based additional protecting groups being compatible with this protection scheme Other linkers which are suitable for the process of the invention include the super acid labile 4-(2,4-dιmethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, Rink, H Tetrahedron Lett 1987, 28, 3787-3790), where the removal of the peptide requires 10% acetic acid in DCM or 0 2% tnfluoroacetic acid in DCM, the 4-(4-hydroxymethyl-3- methoxyphenoxy)butyπc acid-derived linker (HMPB-hnker, Florsheimer & Riniker, Peptides 1991,1990 131) which is also cleaved with 1%TFA/DCM in order to yield a peptide fragment containing all acid labile side- chain protective groups, and, in addition, the 2-chlorotπtylchloπde linker (Barlos et al , Tetrahedron Lett 1989, 30, 3943-3946), which allows the peptide detachment using a mixture of glacial acetic acid/tπfluoroethanol/DCM (1 2 7) for 30 mm
Suitable protecting groups for amino acids and, respectively, for their residues are, for example,
for the amino group (as is present e g also in the side-chain of lysine) Cbz benzyloxycarbonyl
Boc tert.-butyloxycarbonyl
Fmoc 9-fluorenylmethoxycarbonyl
Alloc allyloxycarbonyl
Teoc trimethylsilylethoxycarbonyl
Tec trichloroethoxycarbonyl
Nps o-nitrophenylsulfonyl;
Trt triphenymethyl or rrityl
- for the carboxyl group (as is present e. g. also in the side-chain of aspartic and glutamic acid) by conversion into esters with the alcohol components
tBu tert.-butyl
Bn benzyl
Me methyl
Ph phenyl
Pac Phenacyl
Allyl
Tse trimethylsilylethyl
Tee trichloroethyl;
for the guanidino group (as is present e. g. in the side-chain of arginine)
Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl Ts tosyl (i. e. p-toluenesulfonyl)
Cbz benzyloxycarbonyl
Pbf pentamethyldihydrobenzofuran-5-sulfonyl
for the hydroxy group (as is present e. g. in the side-chain of threonine and serine)
tBu tert.-butyl
Bn benzyl
Trt trityl
- and for the mercapto group (as is present e. g. in the side-chain of cysteine)
Acm acetamidomethyl tBu tert.-butyl Bn benzyl
Trt tπtyl
Mtr 4-methoxytπtyl
The 9-fluorenylmethoxycarbonyl- (Fmoc)-protected amino acid deπvatives are preferably used as the building blocks for the construction of the template-fixed β-hairpin loop mimetics of formula I For the deprotection, I e cleaving off of the Fmoc group, 20% pipeπdine in DMF or 2% DBU/2% pipeπdine in DMF can be used
The quantity of the reactant, l e of the ammo acid derivative, is usually 1 to 20 equivalents based on the milhequivalents per gram (meq/g) loading of the functionalized solid support (typically 0 1 to 2 85 meq/g for polystyrene resins) originally weighed into the reaction tube Additional equivalents of reactants can be used if required to dnve the reaction to completion in a reasonable time The reaction tubes, in combination with the holder block and the manifold, are reinserted into the reservoir block and the apparatus is fastened together Gas flow through the manifold is initiated to provide a controlled environment, for example, nitrogen, argon, air and the like The gas flow may also be heated or chilled prior to flow through the manifold Heating or cooling of the reaction wells is achieved by heating the reaction block or cooling externally with lsopropanol/dry ice and the like to bring about the desired synthetic reactions Agitation is achieved by shaking or magnetic stirnng (within the reaction tube) The prefened workstations (without, however, being limited thereto) are Labsource's Combi-chem station and MultiSyn Tech's-Syro synthesizer
Amide bond formation requires the activation of the α-carboxyl group for the acylation step When this activation is being earned out by means of the commonly used carbodnmides such as dicyclohexylcarbodnmide (DCC, Sheehan & Hess, J Am Chem Soc 1955, 77, 1067-1068) or dnsopropylcarbodiimide (DIC, Sarantakis et al Biochem Biophys Res Commun 1976, 73, 336-342), the resulting dicyclohexylurea is insoluble and, respectively, dnsopropylurea is soluble m the solvents generally used In a variation of the carbodπmide method 1-hydroxybenzotπazole (HOBt, Konig & Geiger, Chem Ber 1970, 103, 788-798) is included as an additive to the coupling mixture HOBt prevents dehydration, suppresses racemization of the activated amino acids and acts as a catalyst to improve the sluggish coupling reactions Certain phosphonium reagents have been used as direct coupling reagents, such as benzotπazol-l-yl-oxy-tπs-(dιmethylamιno)-phosphonιum hexafluorophosphate (BOP) (Castro et al , Tetrahedron Lett 1975, 14, 1219-1222, Synthesis, 1976, 751-752), or benzotπazol-1-yl-oxy-tπs-pynolιdιno-phosphonιum hexaflurophoshate (Py-BOP, Coste et al , Tetrahedron Lett 1990, 31, 205-208), or 2-(lH-benzotπazol-l-yl-)l,l,3,3-tetramethyluronιum terafluoroborate (TBTU), or hexafluorophosphate (HBTU, Knon et al , Tetrahedron Lett 1989, 30, 1927-1930), these phosphonium reagents are also suitable for in situ formation of HOBt esters with the protected amino acid derivatives More recently diphenoxyphosphoryl azide (DPP A) or 0-(7- aza-benzotπazol-l-yl)-N,N,N',N'-tetramethyluronιum tetrafluoroborate (TATU) or 0-(7-aza- benzotπazol-l-yl)-N,N,N',N'-tetramethyluronιum hexafluorophosphate (HATU)/7-aza-l -hydroxy benzotnazole (HOAt, Carpino et al , Tetrahedron Lett 1994, 35, 2279-2281) have also been used as coupling reagents
Due to the fact that near-quantitative coupling reactions are essential it is desirable to have experimental evidence for completion of the reactions The ninhydπn test (Kaiser et al , Anal Biochemistry 1970, 34, 595), where a positive color-metric response to an aliquot of resin-bound peptide indicates qualitatively the presence of the primary amme, can easily and quickly be performed after each coupling step Fmoc chemistry allows the spectrophotometπc detection of the Fmoc chromophore when it is released with the base (Meienhofer et al , Int J Peptide Protein Res 1979, 13, 35-42)
The resm-bound intermediate within each reaction tube is washed free of excess of retained reagents, of solvents, and of by-products by repetitive exposure to pure solvent(s) by one of the two following methods
1) The reaction wells are filled with solvent (preferably 5 ml), the reaction tubes, in combination with the holder block and manifold, are immersed and agitated for 5 to 300 minutes, preferably 15 minutes, and drained by gravity followed by gas pressure applied through the manifold inlet (while closing the outlet) to expel the solvent,
2) The manifold is removed from the holder block, aliquots of solvent (preferably 5 ml) are dispensed through the top of the reaction tubes and drained by gravity through a filter into a receiving vessel such as a test tube or vial
Both of the above washing procedures are repeated up to about 50 times (preferably about 10 times), monitoring the efficiency of reagent, solvent, and byproduct removal by methods such as TLC, GC, or inspection of the washings
The above described procedure of reacting the resin-bound compound with reagents within the reaction wells followed by removal of excess reagents, by-products, and solvents is repeated with each successive transformation until the final resin-bound fully protected linear peptide has been obtained Before this fully protected linear peptide is detached from the solid support, it is possible, if desired, to selectively deprotect one or several protected functional group(s) present m the molecule and to appropriately substitute the reactive group(s) thus liberated To this effect, the functional group(s) m question must initially be protected by a protecting group which can be selectively removed without affecting the remaining protecting groups present Alloc (allyloxycarbonyl) is an example for such a protecting group for amino which can be selectively removed, e g by means of Pd° and phenylsilane in CH2C12) without affecting the remaining protecting groups, such as Fmoc, present in the molecule The reactive group thus liberated can then be treated with an agent suitable for introducing the desired substituent Thus, for example, an amino group can be acylated by means of an acylating agent corresponding to the acyl substituent to be introduced
Detachment of the fully protected linear peptide from the solid support is achieved by immersion of the reaction tubes, m combination with the holder block and manifold, in reaction wells containing a solution of the cleavage reagent (preferably 3 to 5 ml) Gas flow, temperature control, agitation, and reaction monitoring are implemented as described above and as desired to effect the detachment reaction The reaction tubes, in combination with the holder block and manifold, are disassembled from the reservoir block and raised above the solution level but below the upper hp of the reaction wells, and gas pressure is applied through the manifold inlet (while closing the outlet) to efficiently expel the final product solution into the reservoir wells The resin remaining in the reaction tubes is then washed 2 to 5 times as above with 3 to 5 ml of an appropriate solvent to extract (wash out) as much of the detached product as possible The product solutions thus obtained are combined, taking care to avoid cross-mixing The individual solutions/extracts are then manipulated as needed to isolate the final compounds Typical manipulations include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization or additional reactions in solution
The solutions containing fully protected linear peptide derivatives which have been cleaved off from the solid support and neutralized with a base, are evaporated Cyclization is then effected in solution using solvents such as DCM, DMF, dioxane, THF and the like Various coupling reagents which were mentioned earlier can be used for the cyclization The duration of the cyclization is about 6-48 hours, preferably about 24 hours The progress of the reaction is followed, e g by RP-HPLC (Reverse Phase High Performance Liquid Chromatography) Then the solvent is removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a solvent which is not miscible with water, such as DCM, and the solution is extracted with water or a mixture of water-miscible solvents, in order to remove any excess of the coupling reagent Before removing the protecting groups from the fully protected cyclic peptide, it is possible, if desired, to form an interstrand linkage between side-chains of appropnate amino acid residues at opposite positions of the β-strand region
Interstrand linkages and their formation have been discussed above, in connection with the explanations made regarding groups of the type H which can, for example, be disulfide bndges formed by cysteines and homocysteines at opposite positions of the β-strand, or glutamic and aspartic acid residues linking ornithines and, respectively, lysines located at opposite β-strand positions by amide bond formation The formation of such interstrand linkages can be effected by methods well known in the art
Finally, the fully protected peptide derivative of type I is treated with 95% TFA, 2 5% H20, 2 5% TIS or another combination of scavengers for effecting the cleavage of protecting groups The cleavage reaction time is commonly 30 minutes to 12 hours, preferably about 2 hours Thereafter most of the TFA is evaporated and the product is precipitated with ether/hexane (1 1) or other solvents which are suitable therefor After careful removal of the solvent, the cyclic peptide derivative obtained as end- product can be isolated Depending on its puπty, this peptide derivative can be used directly for biological assays, or it has to be further purified, for example by preparative HPLC
As mentioned earlier, it is thereafter possible, if desired, to convert a fully deprotected product thus obtained into a pharmaceutically acceptable salt or to convert a pharmaceutically acceptable, or unacceptable, salt thus obtained into the conespondmg free compound of formula I or into a different, pharmaceutically acceptable, salt Any of these operations can be earned out by methods well known
The starting materials used in the process of the invention, pre-startmg materials therefore, and the preparation of these starting and pre-starting materials will now be discussed in detail
Building blocks of type A can be synthesized according to the literature methods described below The corresponding amino acids have been described either as unprotected or as Boc- or Fmoc- protected racemates, (D)- or (L)-ιsomers It will be appreciated that unprotected amino acid building blocks can be easily transformed into the corresponding Fmoc-protected amino acid building blocks required for the present invention by standard protecting group manipulations Reviews describing general methods for the synthesis of α-ammo acids include R Duthaler, Tetrahedron (Report) 1994, 349, 1540-1650, R M Williams, "Synthesis of optically active α-amino acids", Tetrahedron Organic Chemistry Series, Vol 7, J E Baldwin, P D Magnus (Eds ), Pergamon Press , Oxford 1989 An especially useful method for the synthesis of optically active α-amino acids relevant for this invention includes kinetic resolution using hydrolytic enzymes (M A Verhovskaya, I A Yamskov, Russian Chem Rev 1991, 60, 1163-1179, R M Williams, "Synthesis of optically active α-amino acids", Tetrahedron Organic Chemistry Series, Vol 7, J E Baldwin, P D Magnus (Eds ), Pergamon Press , Oxford 1989, Chapter 7, p 257-279) Hydrolytic enzymes involve hydrolysis of amides and nitnles by ammopeptidases or mtrilases, cleavage of N-acyl groups by acylases, and ester hydrolysis by lipases or proteases It is well documented that certain enzymes will lead specifically to pure (L)-enantιomers whereas others yield the corresponding (D)-enantιomers (e g R Duthaler, Tetrahedron Report 1994, 349, 1540-1650, R M Williams, "Synthesis of optically active α-amino acids", Tetrahedron Organic Chemistry Series, Vol 7, J E Baldwin, P D Magnus (Eds ), Pergamon Press , Oxford 1989)
Al See D Ben-Ishai, Tetrahedron 1977, 33, 881-883, K Sato, A P Kozikowski, Tetrahedron Lett 1989, 30, 4073-4076, J E Baldwin, C N Farthing, A T Russell, C J Schofield, A C Spirey, Tetrahedron Lett 1996, 37, 3761-3767, J E Baldwin, R M Adlington, N G Robinson, J Chem Soc Chem Commun 1987, 153-157, P Wιpf, Y Uto, Tetrahedron Lett 1999, 40, 5165-5170, J E Baldwin, R M Adlington, A O'Neil, A C Spirey, J B Sweeney, J Chem Soc Chem Commun 1989, 1852-1854 (for R'= H, R2= H), T Hiyama, Bull Chem Soc Jpn 1974, 47, 2909-2910, T Wakamiya, K Shimbo, T Shiba, K Nakajima, M Neya, K Okawa, Bull Chem Soc Jpn 1982, 55, 3878-3881 , 1 Shima, N Shimazaki, K Imai, K Hemmi, M Hashimoto, Chem Pharm Bull 1990, 38, 564-566, H Han, J Yoon. K D Janda, J Org Chem 1998, 63, 2045-2048 (R'= H, R2= Me), J Legters, G H Willems, L Thijs, B Zwannenburg, Reel Trav Chim Pays-Bas 1992, 777, 59-68
(R'= H, R2= hexyl), J Legters, L Thijs, B Zwannenburg, Re Trav Chim Pays-Bas 1992, 77 , 16- 21, G A Molander, P J Stengel, J Org Chem 1995, 27, 6660-6661 (Rl= H, R2= Ph), I Funaki, L Thijs, B Zwannenburg, Tetrahedron 1996, 52, 9909-9924 (R'= H, R2= Bn), A S Pepito, D C Dιttmer, J Org Chem 1997, 62, 7920-7925 , (R'= H, R2= CH2OH), M Egh, A S Dreiding, Helv Chim Acta 1986, 69, 1442-1460 (R2= CH(OH)CH2OH), M Carduccu, S Fioravanti, M A Loreto, L Pellacam, P A Tardella, Tetrahedron Lett 1996, 37, 3777-3778, F J Lakner, L P Hager, Tetrahedron Asymmetry 1997, 21, 3547-3550 (R'= Me, R = H, Me), G A Molander, P J Stengel, Tetrahedron 1997, 26, 8887-8912, M A Loreto, F Pompei, P A Tardella, D Tofani, Tetrahedron 1991, 53, 15853-15858 (R'= Me, R2= CH2SιMe3), H Shao, J K Rueter, M Goodman, ./ Org Chem 1998, 63, 5240-5244 (R'= Me, R2= Me)
A2 See A Rao, M K Gurjar, V Vivarr, Tetrahedron Asymmetry 1992, 3, 859-862, R L Johnson, G Rayakumar, K -L Yu, R K Misra, -/ Med Chem 1986, 29, 2104-2107 (R'= H, R2= H), J E Baldwin, R M Adlington, R H Jones, C J Schofield, C Zarcostas, J Chem Soc Chem Commun 1985, 194-196, J E Baldwin, R M Adlington, R H Jones, C J Schofield, C Zarcostas,
Tetrahedron 1986, 42, 4879-4888 (R'= H, R2= CH2OH, CH2CHO, CH2CH2COOH, CH2CH2OH), A P Kozikowski, W Tueckmantel, I J Reynolds, J T Wroblewski, J Med Chem 1990, 35, 1561 - 1571, A P Kozikowski, W Tueckmantel, Y Liao, H Manev, S Ikonomovic J T Wroblenski, J Med Chem 1993, 36, 2706-2708 (R'= H, R2= CH2OH, CHCONH2, CONHCH2COOH, COOtBu), D Seebach, T Vettiger, H -M Muller, D Plattner, W Petter, Liebigs Ann Chem 1990, 687-695 (R'= ArylCH(OH), R2=H), D Seebach, E Dziadulewicz, L Behrendt, S Cantoreggi, R Fitzi, Liebigs Ann Chem 1989, 1215-1232 (R'= Me, Et, R2=H)
A3 See A P Kozikowski, Y Liao, W Tueckmantel, S Wang, S Pshsenichkin, Bioorg Med Chem Lett 1996, 6, 2559-2564 (R'= H, R2= CHCHO, CH2OH, CH2CH2OH, CH2COOH, COOH), Isono, J Am Chem Soc, 1969, 91, 7490 (R'= H, R2= Et), P J Blythin, M J Green, M J Mary, H Shue, Org Chem 1994, 59, 6098-6100, S Hanessian, N Bernstein, R -Y Yang, R Maquire, Bioorg Chem Lett 1994, 9, 1437-1442 (R'= H, R2= Ph)
A4 See G Emmer, Tetrahedron 1992, 48, 7165-7172, M P Meyer, P L Feldman, H Rapoport. J Org Chem 1985, 50, 5223-5230 (R'= H, R2= H), A J Bose, M S Manhas, J E Vincent, I F Fernandez, J Org Chem 1982, 47, 4075-4081 (R'= H, R2= NHCOCH2OPh), D L Boger, J B
Meyers, J Org Chem 1991, 56, 5385-5390 (R'= H, R2= NHCOCH2Ph), K -D Kampe, Tetrahedron Lett 1969, 117-120 (R'= CH2OH, R2= Ph), M D Andrews, M G Maloney, K L Owen, J Chem Soc Perkin Trans 1, 1996, 227-228 (R'= CH2OH, R2= H)
A5 See C Bisang, C Weber, J Inglis, C A Schiffer, W F van Gunsteren, J A Robinson J Am Chem Soc 1995, 777, 7904 (R'= CH3, R = H), S Takano, M Moπja, Y Iwabuki, K Ogasawara, Tetrahedron Lett 1989, 30, 3805-3806 (R'= H, R2= COOH), M D Bachi, R Breiman, H Meshulam, -/ Org Chem 1983, 48, 1439-1444 (R'= H, R2= CH(Et)COOH), D S Kemp, T P Cuπan, Tetrahedron Lett 1988, 29, 4931-4934, D S Kemp, T P Curran, W M Davies. J Org Chem 1991, 56, 6672-6682 (R'= H, R2= CH2OH), F Manfre, J -M Kem, J -F Biellmann, J Org Chem 1992, 57, 2060-2065 (R'= H, R2= H, CH=CH2, CCH), B W Bycroft, S R Chabra, J Chem Soc Chem Commun 1989, 423-425 (R'= H, R2= CH2COOtBu, Y Xu, J Choi, M I Calaza, S Turner, H Rapoport. J Org Chem 1999, 64, 4069-4078 (R'= H, R2= 3-pyπdyl), E M Khahl, W j Ojala. A Pradham, V D Nair, W B Gleason, J Med Chem 1999, 42, 628-637, E M Khahl, N L Subasinghe, R L Johnson, Tetrahedron Lett 1996, 37, 3441-3444 (R'= allyl, R2= H), A DeNicola, J -L Luche, Tetrahedron Lett 1992, 33, 6461 -6464, S Thaisπvongs, D T Pals, J A Lawson, S Turner, D W Hams, J Med Chem 1987, 30, 536-541 , E M Khahl, N L Subasinghe, R L Johnson, Tetrahedron Lett 1996, 57, 3441-3444, A Lewis, J Wilkie, T J Rutherford, D Gam, J Chem Soc Perkin Trans 1, 1998, 3777-3794 (R'= Me, R2= H), A Lewis, J Wilkie, T J Rutherford, D Gam, J Chem Soc Perkin Trans 1, 1998, 3777-3794 (R>= CH2COOMe, R2= H), N L
Subasinghe, E M Khahl.R L Johnson, Tetrahedron Lett 1997, 38, 1317-1320 (R'= CH2CHO, R2= H), D J Witter, S J Famiglietti, J C Gambler, A L Castelhano, Bioorg Med Chem Lett 1998, 8, 3137-3142, E H Khahl, W H Ojada, A Pradham, V D Nair, W B Gleason, J Med Chem 1999, 42, 628-637 (R'= CH2CH2CHO, R2= H)
A6 See DeNardo, Farmaco Ed Sci 1977, 32, 522-529 (R'= H, R3= H), P J T Floπs, N Terhuis, H Hiemstra, N W Speckamp, Tetrahedron, 1993, 49, 8605-8628, S Kanemasa, N Tomoshige, O Tsuge, -Sw./ Chem Soc Jpn 1989, 62, 3944-3949 (R'= H, R3= H), Sucrow, Chem Ber 1979, 772, 1719
A7 See Fichter. J rø/ - Chem 1906, 74, 310 (R'=Me, R4= Ph)
A8 See L Lapantsanis, G Mihas, K Froussios, M Kolovos, Synthesis 1983, 641-673, H Nedev, H Nahaπsoa, Tetrahedron Lett 1993, 54, 4201-4204, D Y Jackson, C Quan, D R Artιs, T Rawson, B Blackburn, J Med Chem 1997, 40, 3359-3368, D Konopinska, H Bartosz-Bechowski, G Rosinski, W Sobotka, Bull Pol Acad Sci Chem 1993, 41, 27-40, J Hondrehs, G Lonergan, S Voliotis, J Matsukas, Tetrahedron 1990, 46, 565-576, T Nakamura, H Matsuyama, H Kanigata, M Iyoda, -/ Org Chem 1992, 57, 3783-3789, C E O'Connell, K Ackermann, C A Rowell, A Garcia, M D Lewis, C E Schwartz, Bioorg Med Chem Lett 1999, 9, 2095-2100, G Lowe. T Vilaivan, -/ Chem Soc Perkin Trans 1997, 547-554, B Belher, I McCourt-Tranchepam, B Ducos, S Danascimenta, H Mundal, J Med Chem 1997, 40, 3947-3956, M Peterson, R Vince J Med Chem 1991, 34, 2787-2797, E M Smith, G F Swiss, B R Neustadt, E H Gold, J A Sommer, -/ Med Chem 1988, 57, 875-885, E Rubini, C Gilon, Z Sehnger, M Chorev, Tetrahedron 1986, 42, 6039- 6045 (R'= H, R5= OH), C R Noe, M Knollmueller, H Voellenkle, M Noe-Letschnig, A Weigand, J Muh\, Pharmazie, 1996, 51, 800-804 (R'= CH3, R5= OH), J Kitchin, R C Berthell. N Cammack, S Dolan, D N Evans, J Med Chem 1994, 57, 3703-3716, D Y Jackson, C Quan, D R Artιs, T Rawson, B Blackburn, J Med Chem 1997, 40, 3359-3368 (R'= H, R5= OBn), J E Baldwin, A R Field, C C Lawrence, K D Memtt, C J Schofield, Tetrahedron Lett 1993, 34, 7489-7492, K Hashimoto, Y Shima, H Shirahama, Heterocycles 1996, 42, 489-492 (R'= H, R5= OTS), T R Webb. C Eigenbrot, J Org Chem 1991, 56, 3009-3016, D C Cafferty, C A Slate, B M Nakhle, H D Graham, T L Anstell, Tetrahedron 1995, 57, 9859-9872 (R'= H, R5= NH2), T R Webb, C Eigenbrot, J Org Chem 1991, 56, 3009-3016 (R'= H, R5= CH2NH2), J K Thottathil, J L Moniot, Tetrahedron Lett 1986, 27, 151-154 (R - H, Rs= Ph), K Plucinska, T Kataoka, M Yodo, W Cody, J Med Chem 1993, 56, 1902-1913 (R'= H, R5= SBn), J Krapcho, C Turk, D W Cushman, J R Powell, - Med Chem 1988, 57, 1 148-1160 (R'= H, R5= SPh), A J Verbiscar, B Witkop, -/ Org Chem 1970, 55, 1924-1927 (R'= H, R5= SCH2(4-0Me)C6H4), S I Klein, J M Denner, B F Mohno, C Gardner, R D'Ahsa, Bioorg Med Chem Lett 1996, 6, 2225-2230 (R'= H, R5=
0(CH2)3Ph), R Zhang, F Brownewell, J S Madalengoita, Tetrahedron Lett 1999, 40, 2101-27 0 (R'= H, R5= CH2COOBn) A9 See Blake, J Am Chem Soc 1964, 86, 5293-5297, J Cooper, R T Gallagher, D T Knight, J Chem Soc Chem Perkin Trans 1, 1993, 1313-1318, D W Knight, A W Sibley, J Chem Soc Perkin Trans 1, 1997, 2179, 2188 (R'= H, Rδ= H), Blake, J Am Chem Soc 1964, 86, 5293-5297, Y Yamada, T Ishn, M Kimura, K Hosaka, Tetrahedron Lett 1981, 1353-1354 (R'= H, R6= OH), Y Umio, Yakugaku Zasshi, 1958, 78, 727 (R'= H, R6= iPr), Miyamoto, Yakugaku Zasshi, 1957, 77, 580- 584, Tanaka, Proc Jpn Acad 1957, 53, 47-50 (R'= H, R6= CH(CH3)CH2N(CH3)2), L E Overman, B N Rodgers, J E Tellew, W C Trenkle, J Am Chem Soc 1997, 779, 7159-7160 (R'= H, R6= allyl), Ohki, Chem Pharm Bull 1976, 24, 1362-1369 (R'= CH3, R6= H)
A10 See j Mulzer, A Meier, J Buschmann, P Luger, Synthesis 1996, 123-132 (R'= H, R7=
CH=CH2), J Cooper, P T Gallagher, D W Knight, J Chem Soc Chem Commun 1988, 509-510, E Gotschι, C Jenny, P Reindl, F Rιckhn, He/v Chim Acta 1996, 79, 2219-2234 (R'= Η, R7= OH), N A Sasaki, R Pauh, C Fontaine, A Chiarom, C Riche, P Potier, Tetrahedron Lett 1994, 55, 241- 244 (R'= H, R7= COOH), R Cotton, A N C Johnstone, M North, Tetrahedron 1995, 57, 8525-8544 (R'= H, R7= COOMe), J S Sabol, G A Flynn, D Fπedπch, E W Huber, Tetrahedron Lett 1997, 38, 3687-3690 (R!= H, R7= CONH2), P P Waid, G A Flynn, E W Huber, J S Sabol, Tetrahedron Lett 1996, 37, 4091-4094 (R'= H, R7= (4-BnO)C6H4), N A Sasaki, R Pauh, P Potier, Tetrahedron Lett 1994, 35, 237-240 (R'= H, R7= S02Ph), R J Heffner, J Jiang, M Jouillie, J Am Chem Soc 1992, 114, 10181-10189, U Schmidt, H Gπesser, A Lieberknecht, J Hausler, Angew Chem 1981, 93, 272-273 (R'= H, R7= OAryl), H Mosberg, A L Lomize, C Wang, H Kroona, D L Heyl, J Med Chem 1994, 57, 4371-4383 (R'= H, R7= 4-OH H4), S A Kolodziej. G V Nikiforovich, R Sceean, M -F Lignon, J Martinez, G R Marshall, J Med Chem 1995, 55, 137-149 (R'= H, R7= SCH2(4-Me)C6H4)
All See Kuhn, Osswald, Chem Ber 1956, 59, 1423-1434, Patchett, Wιtkop, J Am Chem Soc
1957, 79, 185-189, Benz, He/v Chim Acta 1974, 57, 2459-2475, P Wessig, Synlett, 1999, 9, 1465- 1467, E M Smit. G F Swiss, B R Neustadt, E Η Gold, j A Sommer, -/ Med Chem 1988, 57, 875-885, J Krapcho, C Turk, D W Cushman, j R Powell, j M DeFoπest, J Med Chem 1988, 57, 1148 (R'= Η, R6= Η), D Benlshai, S Ηirsh, Tetrahedron 1988, 44, 5441-5450 (R'= Η, R6= CΗ3), M W Holladay. C W Lin, C S Garvey, D G Wιtte, J Med Chem 1991, 34, 455-457 (R'= H, R6= allyl), P Barralough, P Hudhomme, C A Spray, D W Young, Tetrahedron 1995, 57, 4195- 4212 (R'= H, R6= Et), J E Baldwin, M Rudolf ', Tetrahedron Lett 1994, 35, 6163-6166, J E Baldwin, S J Bamford, A M Fryer, M Rudolf, M E Wood, Tetrahedron 1997, 53, 5233-5254 (R'= H, R6= CH2COOtBu), P Gill, W D Lubell, 7 Org Chem 1995, (JO, 2658-2659 (R'= H, R6= CH3, Bn, allyl, CH2COOMe), M J Blanco, F J Sardina, J Org Chem 1998, 63, 341 1-3466 (R'= H, R6= OCH2OMe) A12 See Ahmed, Cheeseman, Tetrahedron 1977, 33, 2255-2257, J S New, J P Yevich, J Heterocycl Chem 1984, 27, 1355-1360, R Kikumoto, Y Tamao, K Ohkubo, T Tezuka, S Tonomura, -/ Med Chem 1980, 25, 1293-1299, C J Blankley, J S Kaltenbronn, D E DeJohn, A Werner, L R Bennett, J Med Chem 1987, 30, 992-998, S Klutcho, C J Blankley, R W Fleming, J M Hinkley, R E Werner, -/ Med Chem 1986, 29, 1953-1961 (R'= H, R8= H), L J Beeley, C J M Rockwell, Tetrahedron Lett 1990, 57, 417-420 (R'= COOEt, R8= H)
A13 See G Flouret, W Bπeher, T Majewski, K Mahan, J Med Chem 1991, 43, 2089-2094, G Gahendo, P Gπeco, E Peπssuti, V Santagada, Farmaco, 1996, 57, 197-202, D F McComsey, M J Hawkins, P Andrade-Gordon, M F Addo, B E Maryanoff, Bioorg Med Chem Lett 1999, 9, 1423- 1428, G B Jones, S B Heaton, B J Chapman, M Guzel, Tetrahedron Asymmetry 1997, 5, 3625- 3636, M Asami, H Watanabe, K Honda, S Inoue, Tetrahedron Asymmetry 1998, 9, 4165-4174, K Gross, Y M Yun, P Beak, J Org Chem 1997, 62, 7679-7689 (R'= H, R6= H, R8= H), K Gross, Y M Yun, P Beak, J Org Chem 1997, 62, 7679-7689 (R'= H, R6= H, R8= 6-C1), Ch Noe, M Knollmueller, C Schoedl, M L Berger, Sci Pharm 1996, 64, 577-590, E Reiman, W Erdle, H Unger, Pharmazie, 1994, 54, 418-421 (R'= H, R6= CH2COOH, R8= H), V Collot, M Schmitt, A K Marwah, B Norberg, J -J Bourgignon, Tetrahedron Lett 1997, 55, 8033-8036 (R'= H, R6= Ph, R8= H), L V Dunkerton. H Chen, B P McKilhcan, Tetrahedron Lett 1988, 29, 2539-2542 (R' = C(CH3)2CH=CH2, R6= H, R8= H), E J Corey, J Am Chem Soc 1970, 92, 2476-2488, Neunhoeffer, Lehmann, Chem Ber 1961, 94, 2960-2963 (R'= CH3, R6= H, R8= H)
A14 Amino acids of type A14 can be made according to Scheme 1 Scheme 1
i NaH, BrCHO JCOOMe, DMF, n LιOHx1 H20, MeOH, H20, in polyphosphoπc acιd(PPA), iv NaH, CICOOMe, THF, v enzymatic resolution (e g lipase), vi NaOH, MeOH, H20, heat, vii FmocOSu, Na2C03aq , dioxane A15 See D S Perlow, J M Erb, N P Gould, R D Tung, R M Freidinger, J Org Chem 1992, 57, 4394-4400, D Y Jackson, C Quan, D R Artis. T Rawson, B Blackburn, J Med Chem 1997, 40, 3359-3368 (R'= H, R2= H), H H Wasserman, K Rodπgues, K Kucharczyk, Tetrahedron Lett 1989, 30, 6077-6080 (R'= H, R2= COOH)
A16 See Beyerman, Boekee, Reel Trav Chim Pays-Bas, 1959, 78, 648-653, M E Freed, A R Day, Org Chem 1960, 25, 2105-2107, D R Adams, P D Bailey, I D Collier, J D Heferman, S Stokes, -/ Chem Soc Chem Commun 1996, 349-350, J E Baldwin, R M Adlington, C R A Godfrey, D W Collins, J D Vaughan, Chem Soc Chem Commun 1993, 1434-1435, Y Matsumura, Y Takeshima, H Ohita, Bull Chem Soc Jpn 1994, 67, 304-306 (R'= H, R6= H), C Herdeis, W Engel, Arch Pharm 1991, 324, 670 (R'= COOMe, R6= CH3)
A17, A18 See C R Davies, J S Davies, -/ Chem Soc Perkin Trans 7, 19 '6, 2390-2394, K Bevan, J Chem Soc C, 1971, 514-522, K Umezawa, K Nakazawa, Y Ikeda, H Naganawa, S Kondo, Org Chem 1999, 64, 3034-3038 (R'= R3= H), P D Williams, M G Bock, R D Tung, V M
Garsky, D S Parlow, J Med Chem, 1992, 35, 3905-3918 , K Tamaki, K Tanzawa, S Kuπhara, T Oikawa, S Monma, Chem Pharm Bull 1995, 43, 1883-1893 (R'= RS= H , R3= COOBn) , K J Hale, J Cai. V Dehsser, S Manaviazar, S A Peak, Tetrahedron 1996, 52, 1047-1068 , M H Chen, O P Goel, J -W Hyun, J Magano, J R Rubin, Bioorg Med Chem Lett 1999, 9, 1587-1592 (R'= RS= H, R3= COOtBu), R Baenteh, I Bran, P Hall, R Mettemich, Tetrahedron Lett 1999, 40, 2109-2112
(R'= R5= H, R3= COR), K J Hale, N Jogiya, S Manaviazar, Tetrahedron 1998, 39, 7163-7166 (R'= H, R3= COOBn, R5= OBn), T Kamenecka, S J Damshewsky, Angew Chem Int Ed Engl 1998, 37, 2995-2998(R'= H, R3= COO(CH2)2SιMe3, R5= OSιMe2tBu
A19 See Beilstein, Registry Number 648833 (R'=R =R8=H) Compounds of this type can be prepared according to Scheme 2
Scheme 2
i NaH, CH2(COOMe)2, DMSO, n NaH, Rη-X, DMSO, HI NaOHaq , MeOH, 75°, iv DBU, Mel, DMF, v LDA, BocN=NBoc, vi TFA, CH2CI2, vιι CbzCI, Na2C03aq , dioxane, vin enzymatic resolution
(e g pase), then DBU, Mel, DMF, ix NaH, R4-X, THF, x Pd/C, H2, EtOH, xi LιOHx1 H20, MeOH,
H20, xii FmocOSu,Na2C03aq , dioxane
A20 See D Hagiwara, H Miyake, N Igari, M Kanno, Y Maeda, J Med Chem 1994, 37, 2090- 2099 (R'= H, R9= OH), Y Arakawa, M Yasuda, M Ohnishi, S Yoshifuji, Chem Pharm Bull 1997, 45, 255-259 (R'= H, R9= COOH), P J Munay, I D Starkey, Tetrahedron Lett 1996, 57, 1875-1878 (R'= H, R9= (CH2)2NHCOCH2Ph), K Clinch, A Vasella, R Schauer, Tetrahedron Lett 1987, 25, 6425-6428 (R'= H, R9= NHAc)
A21 See A Golubev, N Sewald, K Burger, Tetrahedron Lett 1995, 36, 2037-2040, F Machetti, F M Cordero. F DeSaπo, A Guarna, A Brandi, Tetrahedron Lett 1996, 57, 4205-4208, P L Omstein, D D Schoepp, M B Arnold, J D Leander, D Lodge, J Med Chem 1991, 34, 90-97 , R'=R6=H), P D Leeson, B J Williams, R Baker, T Ludduwahetty, K W Moore, M Rowley, J Chem Soc Chem Commun 1990, 1578-1580, D I C Scopes, N F Hayes, D E Bays, D Belton, J Brain, J Med Chem 1992, 55, 490-501, H Kessler, M Kuehn, T Loschner, Lieb igs Ann Chem 1986, 1-20 (R'=R6=H), C Herdeis, W Engel, Arch Pharm 1992, 7, 419-424 (R'=R6=Bn), C Herdeis, W Engel, Arch Pharm 1992, 411-418 (R'=COOMe, R6=H), C Herdeis, W Engel, Arch Pharm 1992, 419-424 (R'=COOMe, R6=Bn)
A22 See P D Leeson, B J Williams, R Baker, T Ladduwahetty, K W Moore, M Rowley, J Chem Soc Chem Comm 1990, 1578-1580 (R'= H, Rl0= NHOBn) A23 See Beyerman, Boekee, Reel Trav Chim Pays-Bas 1959, 75, 648-653, D R Adams, P D Bailey, I D Collier, J D Heffernan, S Stokes J Chem Soc Chem Commun 1996, 349-350, J E Baldwin, R M Adlington, C Godfrey, D W Collins, J G Vaughan, J Chem Soc Chem Comm 1993, 1434-1435 (R'=R6=H), C Herdeis, W Engel, Arch Pharm 1993, 297-302 (R'=COOMe, R6=H)
A24 See Phenmger, Leonhauser, Chem Ber 1959, 92, 1579-1584, D W Knight, N Lewis, A C Share, D Haigh, J Chem Soc Perkin Trans 1 1998, 22, 3673-3684, J Drummond, G Johnson, D G Nιckell, D F Ortwine, R F Brans, B Welbaum, J Med Chem 1989, 32, 2116-2128, M P Moyer, P L Feldman. H Rapoport, J Org Chem 1985, 50, 5223-5230 (R'=R6=H), McElvam, Laughton, J Am Chem Soc 1951, 75, 448-451 (R'=H, R6=Ph), McElvam, Laughton, J Am Chem Soc 1951, 73, 448-451 (R'=Ph, R6=H),
A25 See L -Y Hu, T R Ryder, S S Nikam, E Millerman, B G Szoke, M F Rafferty, Bioorg Med Chem Lett 1999, 9, 1121-1126, W C Lumma, R D Hartman, W S Saaπ, E L Engelhardt, V J Lotti, C A Stone, J Med Chem 1981, 24, 93-101 , N Hosten, M J O Antenuis, Bull Soc Chim Belg 1988, 97, 48-50, C F Bigge, S J Hays, P M Novak, j T Drummond, G Johnson, T P Bobovski, Tetrahedron Lett 1989, 30, 5193-5191 , B Aebischer, P Frey, H -P Haerter, P L Herrhng, W Muller, Helv Chim Acta 1989, 72, 1043-1051 , W J Hoeckstra, B E Maryanoff, B P Damiano, P Andrade-Gordon, J H Cohen, M J Constanzo, B J Haertlein, L R Hecker, B L Hulshizer. J A Kauffman, P Keane, J e-i Chem 1999, 42, 5254-5265 (R'=H, R"=H) , B D Dorsey, R B Levin, S L McDaniel, J P Vacca, J P Guare, J Med Chem 1994, 57, 3443-3451, M Cheng, B De, S Pikul, N G Almstaed, M G Natchus, M V Anastasio, S J McPhail, C J Snider, Y O Taιwo, L Chen, C M Dunaway, J Med Chem 2000, 43, 369-380, R Kuwano, Y Ito, J Org Chem. 1999, 64, 1232-1237 (R'=H, R"= OOtBu), J Kitchin, R C Bethell, N Cammack, S Dolan, D N Evans, J Med Chem 1994, 37, 3707-3716 (R'=H, Rπ=COOPh), C F Bigge, S J Hays, P M Novak, J T Drummond, G Johnson, T P Bobovski, J Med Chem 1990, 55, 2916- 2924 (R'=H,R"=COOtBu, (CH2)3COOEt, (CH2)3PO(Me)OH, CH2PO(OH)2, (CH2)2PO(OEt)2, (CH2)2PO(OH)2)
Compounds of type A25 can also be prepared according to Scheme 3 Scheme 3
12 13 14 i Lawesson reagent, toluene, 80°, u DBU, Mel, DMF, in NaBH4 or NaCNBH3, MeOH, iv Boc20, THF, v LιOHx1H20, MeOH, H20, vi Pd/C, H2, EtOH, vu FmocOSu, Na2C03aq , dioxane
A26 See Koegel, J Biol Chem 1953, 207, 547 (R'=R12=H)
A27 See G Makara, G R Marshall, Tetrahedron Lett 1997, 55, 5069-5072, R N Patel, A Banerjee, R L Hanson, D B Brzozowski, L W Parker, L J Szarka, Tetrahedron Asymmetry 1999, 10, 31-36 (R'=H, R13=OH, OtBu), J E Johanson, B D Christie, H Rapoport, J Org Chem 1981, 46, 4914-4920, N Moss, J -S Duceppe, J -M- Ferland, j Gauthier, J Med Chem 1996, 39, 2178- 2187 (R'= H , Rl3= CONHMe), G M Makara, G R Marshall, Tetrahedron Lett 1997, 35, 5069- 5072 (R'=H, R13= SCH2(4-MeO)C6H4)
A28 See A Golubev, N Sewald, K Burger, Tetrahedron Lett 1995, 36, 2037-2040, P L Omstein, D D Schoepp, M B Arnold, j D Leander, D Lodge, J Med Chem 1991, 34, 90-97 (R'=R6=H), P D Leeson, B j Williams, R Baker, T Ladduwahetty, K W Moore, M Rowley, J Chem Soc Chem Commun 1990, 22, 1578-1580, C Herdeis, W Engel, Arch Pharm 1991, 324, 670 (R'=H , R6=Me), C Herdeis, W Engel, Arch Pharm 1991, 324, 610 (R'=COOMe, R6=H, Me)
A29 See Kawase, Masami, Chem Pharm Bull 1997, 45, 1248-1253, 1 G C Coutts, J A Hadfield, P R Huddleston, J Chem Res Minψrint, 1987, 9, 2472-2500, 1 G C Coutts, J A Hadfield, P R Huddleston, J Chem Res Mimprint, 1987, 9, 2472-2500, V J Hrubi, W L Cody, A M Castrucci, M E Hadley, Collect Czech Chem Commun 1988, 53, 2549-2573, R T Shuman, R B Rothenberger, C S Campbell, G F Smith, D S Gifford-Moore, P D Gesellchen, J Med Chem 1993, 36, 314-319, M Kawase, Y Okada, H Miyamae, Heterocycles, 1998, 48, 285-294
(R'=R8=H), Kawase, Masami, Chem Pharm Bull 1997, 45, 1248-1253 (R'=H, R8=6,7-(Me02), D F Ortwme. T C Malone, C F Bigge, J T Drummond, C Humblet, -/ Med Chem 1992, 35, 1345- 1370 (R'=H, R8=7-CH2PO(OEt)2), E J Corey, D Y Gin, Tetrahedron Lett 1996, 37, 7163-7166 (R'= CH2SCOOtBu), P Dostert, M Varasi, A DellaToπe, C Monti, V Rizzo, Eur J Med Chim Ther 1992, 27, 57-59 (R'=Me, R8=6,7-(OH)2), Z Czaraocki, D Suh. D B McLean, P G Hultin.W A Szarek, Can J Chem 1992, 70, 1555-1561, B Schonenberger, A Brossι, He/v Chim Acta 1986, 69, 1486-1497 (R'=Me, R8=6-OH, 7-MeO), Hahn, Stiel, Chem Ber 1936, 69, 2627, M Chrzanowska, B Schonenberger, A Brossi, J L Fhppen-Anderson, Helv Chim Acta 1987, 70, 1721-1731 , T Hudhcky, J Org Chem 1981, 46, 1738-1741 (R'=Bn, R8=6,7-(OH)2), A I Meyers, M A Gonzalez, V Strazka, A Akahane, J Guiles, J S Warmus, Tetrahedron Lett 1991, 32, 5501- 5504 (R'=CH2(3,4-methylenedιoxy)C6H3, R8=6,7-(OMe)2)
A30 and A31 can be prepared according to Schemes 4 and 5
Scheme 4
i NaH, tert -butyl N-benzoyl glycinate, DMF, u NaH, Pd(0), toluene, in TFA, CH2CI2, iv polypho- sphonc acid, v NaOHaq ,MeOH, 75°, then HCIaq , vi DBU, Mel, DMF, vn lithium hexamethyl- disilazide.THF chloro trimethylsilane, -78°, then R -X, VIM enzymatic resolutιon(e g lipase), then isolation as methylester DBU, Mel, DMF, ix NaOHaq , MeOH, heat, x FmocOSu,
Na2C03aq , dioxane
Scheme 5
20 (R8 H) 22 23 i Boc20, Na2C03aq , dioxane, n DBU, Mel, DMF, in lithium hexamethyldisilazide, THF, chlorotnmethylsilane, -78°, then R2-X, iivv LLιιOOHHxx11 HH2200,, MMeeOOHH, H20, v TFA, CH2CI2, vi FmocOSu, Na2C03aq , dioxane
A32 can be prepared according to P W Schiller, G Weltrowska, T M -D Nguyen, C Lemieux, N Nga, J Med Chem 1991, 34, 3125-3132, V S Goodfellow, M V Marathe, K G Kuhlman, T D Fitzpatπck, D Cuadrato, J Med Chem 1996, 59, 1472-1484, G Cahendo, F Fioπno, P Gneco, E Peπssutti, S DeLuca, A Guihano, G Santelh, D Cahfano, B Seveπno, V Santagada, Farmacao, 1999, 54, 785-790, V S Goodfellow, M V Marathe, K G Kuhlman, T D Fitzpatπck, D Cuadro, J Med Chem 1996, 39, 1472-1484 (R'= R8= H), D Tourwe, E Mannekens. N T Trang, P Verheyden, H Jaspers, J Med Chem 1998, 41, 5167-5176, A -K Szardemngs, M Gordeev, D V Patel, Tetrahedron Lett 1996, 37, 3635-3638, W Wiczk, K Stachowiak, P Skurski, L Lankiewicz, A Michniewicz, A Roy, J Am Chem Soc 1996, 775, 8300-8307, K Verschuren, G Toth, D Tourwe, M Lebl , G van Bmst, V Hrubi, Synthesis 1992, 458-460 (R'= H, R8= 6-OH), P L Omstein, M B Arnold, N K Augenstein, J W Paschal, J Org Chem 1991, 56, 4388-4392 (R'= H, R8= 6-MeO), D Ma, Z Ma, A P Kozikowski, S Pshemchkin, J T Wroblenski, Bioorg Med Lett 1998, 5, 2447-2450 (R'= H, R8= 6-COOH), U Schollkopf, R Hmrichs, R Lonsky, Angew Chem 1987, 99, 137-138 (R'= Me, R8-H), B O Kammermeier, U Lerch, C Sommer, Synthesis 1992, 1 157-1160 (R'= COOMe, R8=H), T Gees, W B Schweizer, D Seebach, Helv Chim Acta 1993, 76, 2640-2653 (R'= Me, R8=6,7-(Me02)
A33 See Hinton, Mann, J Chem Soc 1959, 599-608
A34 See G P Zecchιnι, M P Paradιsι, J Heterocycl Chem 1919, 16, 1589-1597, S Cenini, J Chem Soc Perkin Trans 1, 1919, 1013-1019, P L Omstein, J W Paschal, P D Gesellchen, J Org Chem 1990, 55, 738-741, G M Ksander, A M Yan, C G Diefenbacher, J L Stanton, -/ Med Chem 1985, 25, 1606-1611 , J A Robl, D S Karanewsky, M M Asaad, Tetrahedron Lett 1995, 56, 1593-1596, S Katayama, N Ae, R Nagata, Tetrahedron Asymmetry 1998, 9, 4295-4300 (R'=R8=H), K Hino, Y Nagai, H Uno, Chem Pharm Bull 1988, 36, 2386-2400 (R'=Me, R8=H)
A35 See Beilstein Registry Numbers 530775, 883013 (R'=R8=H)
A36 See R W Carhng, P D Leeson, A M Moseley, R Baker, A C Foster, -/ Med Chem 1992, 55, 1942-1953, S Kano, T Ebata, S Shιbuya, J Chem Soc Perkin Trans 1, 1980, 2105-21 1 1 (R'=R8=H), R W Carhng, P D Leeson, A M Moseley, R Baker, A C Foster, J Med Chem 1992, 35, 1942-1953 (R'=H, R8=5-C1, 7-C1)
A37 See Nagarajan, Indian J Chem 1973, 77, 1 12 (R'=CH2COOMe, R8=H)
A38 See R Pauly, N A Sasaki, P Potire, Tetrahedron Lett 1994, 35, 237-240, J Podlech, D Seebach, Liebigs Ann Org Bioorg Chem 1995, 7, 1217-1228, K C Nicolaou, G -Q Shi, K Namoto. F Bemal, J Chem Soc Chem Commun 1998, 1757-1758 (R'= H, R2= H) A39 See Beilstein, Registry Number 782885
A40 See F P J C Rutjes, N M Terhuis, H Hiemstra, N W Speckamp, Tetrahedron 1993, 49, 8605-8628 (R'= H, R3= Bn), compounds of this type can be prepared according to Scheme 6
Scheme 6
Cbz- .,.NHBoc ι,ιι N
XOOMe
MeOOC XOOMe
MeOOC"
MeOO
26 27 28 i BocNHNH2, NaCNBH3, MeOH, AcOH, n CbzCI, Et3N, CH2CI2, in TFA, CH2CI2, then pyridine,
DMAP, heat, iv resolution (e g lipase), v DBU, Mel, DMF, vi Lawesson reagent, toluene, 75°, vii DBU, Mel, DMF, VIM NaBH4 or NaCNBH3, MeOH, ix R3 introduced by reductive animation, alkylation or acylation, x LιOHx1 H20, MeOH, H20, xi Pd/C, H2, EtOH, xn FmocOSu, Na2C03aq dioxane
A41 Compounds of this type can be prepared according to Scheme 7
Scheme 7
26 29 30 r resolution (e g lipase), then isolation as methylester DBU, Mel, DMF,
II NaH, R4-X, THF, HI LιOHx1 H20, MeOH, H20, iv Pd/C, H2, EtOH, v FmocOSu, Na2C03aq , dioxane
A42 to A46 Compounds of this type can be prepared according to Schemes 8 to 72 Key intermediate 34 and α-amino acid synthesis involving this building block include R M Williams, M -N Im, Tetrahedron Lett 1988, 29, 6079-6082, R M Williams, M -N Im, J Am Chem Soc 1991, 113, 9276-9286, J F Dellaria, B D Santarsiero, Tetrahedron Lett 1988, 29, 6079-6082, J F Dellaπa, B D. Santarsiero, J Org. Chem. 1989, 54, 3916-3926; J. E. Baldwin, V. Lee, C. J. Schofield, Synlett 1992, 249-251; J. E. Baldwin, V. Lee, C. J. Schofield, Heterocycles 1992, 34, 903-906.
Scheme 8
31 32 33
34 35 36 i: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78°; then R -X; ii: HBr; iii: DBU,
Mel, DMF; iv: DIBAL-H, THF; v: EtOH, pyndinium p-toluenesulfonate, mol.sieves 4A; vi: lithium hexamethyldisilazide, THF, -78°, 33; vii: Pd/C, H2, EtOH; then DBU, Mel, DMF; then TFA, CH2CI2; viii: HCIaq., THF; then Na(OAc)3BH, AcOH, dichloroethane; ix: LiOHx1H20,
MeOH, H20; x: FmocOSu, Na2C03aq., dioxane
Scheme 9
34 40 41 i: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78°; then R -X; ii: HBr; iii: DBU, Mel, DMF; iv: DIBAL-H, THF; v: EtOH, pyridinium p-toluenesulfonate, mol.sieves 4A; vi: lithium hexamethyldisilazide, THF, -78°, 39; vii: Pd/C, H2, EtOH; then DBU, Mel, DMF; then TFA, CH2CI2; viii: HCIaq., THF; then Na(OAc)3BH, AcOH, dichloroethane; viii: Boc20, Et3N, CH2CI2; ix: Bu4NFx10H2O, THF; ix: pyridinium chlorochromate; x: LiOHx1 H20, MeOH, H20; xi: TFA, CH2CI2; xii: FmocOSu, Na2C03aq., dioxane Scheme 10
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v. lithium hexamethyldisilazide, THF, -78°, 43; vi: Pd/C, H2, EtOH; then DBU,
Mel, DMF; then TFA, CH2CI2; vii: HCIaq., THF; then Na(OAc)3BH, AcOH, dichloroethane; viii: LiOHx1H20, MeOH, H20; ix: FmocOSu, Na2C03aq., dioxane
Scheme 11
tBuPh2Si O
46 47
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v: lithium hexamethyldisilazide, THF, -78°, 47; vi: Pd/C, H2, EtOH; then DBU, Mel,
DMF; then TFA, CH2CI2; vii: HCIaq., THF; then Na(OAc)3BH, AcOH, dichloroethane; viii Boc20, Et3N, CH2CI2; ix: Bu4NFx10H2O, THF; x: pyridinium chlorochromate; xi: LiOHx1H20, MeOH, H20; xii: TFA, CH2CI2; xiii: FmocOSu, Na2C03aq., dioxane Scheme 12
K"
OSiPh2tBu OEt l-IV
Br OEt OSiPh2tBu
50 51
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v: lithium hexamethyldisilazide, THF, -78°, 51 ; vi: Pd/C, H2, EtOH; then DBU,
Mel, DMF; then TFA, CH2CI2; vii: HCIaq., THF; then Na(OAc)3BH, AcOH, dichloroethane; viii:
Boc20, Et3N, CH2CI2; ix: Bu NFx10H2O, THF; x: pyridinium chlorochromate; xi: LiOHx1 H20,
MeOH, H20; xii: TFA, CH2CI2; xiii: FmocOSu, Na2C03aq., dioxane
A47: See P. Barraclough, R. D. Farrant, D. Kettle, S. Smith, J Chem. Res. Miniprint 1991, 77, 2876- 2884 (R'=R"=H, Bn, (CH2)2PO(OEt)2).
A48: See A. Nouvet, M. Binard, F. Lamaty, J. Martinez, R. Lazaro, Tetrahedron 1999, 55, 4685-4698 (R'=R12=H).
A49: See M. Y. Kolleganov, I. G. Kolleganova, M. D. Mitrofanova, L. I. Martynenko, P. P. Nazarov, V. I. Spitsyn, Bull. Acad. Sci. USSR Div. Chem. Sci (Engl. Trans.) 1983, 32, 1293-1299; Izv. Akad. Nauk SSSR Ser. Khim. 1983, 6, 1293-1299 ; V. P. Vasilev, T. D. Orlova, S. F. Ledenkov, J Gen. Chem. USSR (Engl. Trans. 1989, 59, 1629-1634; Zh. Obshch. Khim. 1989, 59, 1828-1833 (R'=H; Rl2= CH(COOH)CH2COOH). Compounds of type A49 can also be prepared according to Scheme 13.
Scheme 13
57 i: NaH, CbzNH(CH2)2Br, THF; ii: Pd/C, H2, EtOH; iii: EDCI, CH2CI2, diisopropylethylamin; iv: NaH,
R -.112-X, THF; v: LiOHx1 H20, MeOH, H20; vi: TFA, CH2CI2; vii: FmocOSu, Na2C03aq., dioxane
A50 and A51: Compounds of these types can be prepared according to Schemes 14 and 75. Scheme 14
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v: lithium hexamethyldisilazide, THF, -78°, 59; vi: Pd/C, H2, EtOH; then DBU,
Mel, DMF; then TFA, CH2CI2; vii: HCIaq., THF; then Na(OAc)3BH, AcOH, dichloroethane; viii: LiOHx1 H20, MeOH, H20; ix: FmocOSu, Na2C03aq., dioxane
Scheme 15
c
i: HBr; ii: DBU, Mel, DMF; iii: DIBAH, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v: lithium hexamethyldisilazide, THF, -78°, 63 vi: Pd/C, H2, EtOH; then DBU,
Mel, DMF; then TFA, CH2CI2; vii: HCIaq., THF; then Na(OAc)3BH, AcOH, dichloroethane; viii: Boc20, Et3N, CH2CI2; ix: Bu NFx10H2O, THF; x: pyridinium chlorochromate; xi: LiOHx1 H20, MeOH, H20; xii: TFA, CH2CI2; xiii: FmocOSu, Na2C03aq., dioxane
A53: See P. Barraclough, R. D. Farrant, D. Kettle, S. Smith, J. Chem. Res. Miniprint 1991, 77, 2876- 2884(R'=Rπ=H ; R'=H ; R"= Bn, (CH2)3PO(OH)2); (CH2)3PO(Et)2); J. I. Levin, J. F. DiJoseph, L. M. Killar; A. Sung, T. Walter, Bioorg. Med. Chem. Lett. 1998, 8, 2657-2662 (R1 =H; RΠ= 4CF3OC6H4CO).
A 52 and A54: Compounds of this type can be prepared according to Schemes 16 and 77.
Scheme 16
i: iBuMgCI.THF; ii: NaH, THF; iii: lithium hexamethyldisilazide, THF, chlorotrimetylsilane, -78°; then R6-X; iv: NaOHaq., MeOH, 75°; then HCIaq.; v: DBU, Mel, DMF; vi: lithium hexamethyldisilazide , THF, chlorotrimetylsilane, -78°; then R1-X; vii: resolution (e.g. lipase); then DBU, Mel, DMF; viii: LiOHx1 H20, MeOH, H20; ix: TFA, CH2CI2; x: FmocOSu, Na2C03aq., dioxane
Scheme 17
Me
B
i:NaN3, DMSO; ii: NaH, THF, CH2=CHCOOBn; iii: Pd/C, H2, EtOH; iv: EDCI, CH2CI2, diisopropylethylam ιiinnee;; vv:: NNaaHH,, RR1122--XX,, TTHHFF;; vvii:: LLiiOOHHxx11HH2200,, MMeeCOH, H20; vii: TFA,
CH2CI2; viii: FmocOSu, Na2C03aq., dioxane
A55 and A56: Compounds of this type can be prepared according to Schemes 18 and 79.
Scheme 18
BocHN
i.NaH, THF, CbzNH(CH2)3Br; ii: Pd/C, H2, EtOH; then toluene, heat; iii: resolution (e.g. lipase); iv:
DBU, Mel, DMF; v: NaH, R --XX,, TTHHFF;; vvii:: LLiiOOHHxx11 HH2200,, MMeeOOHH, H20; vii: TFA, CH2CI2; viii: FmocOSu, Na2C03aq., dioxane
Scheme 19
34 87 88 i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, mol. sieves 4A; v: lithium hexamethyldisilazide, THF, -78°, 86; vi: Pd/C, H2, EtOH; then DBU,
Mel, DMF; then TFA, CH2CI2; vii: HCIaq., THF; then Na(OAc)3BH, AcOH, dichloroethane; viii: LiOHx1 H20, MeOH, H20; ix: FmocOSu, Na2C03aq., dioxane
A57: Compounds of this type can be prepared according to Scheme 20.
Scheme 20
i: NaOMe, MeOH; ii: NaH, THF; iii: NaOHaq., MeOH, 75°; then HCIaq.; iv: DBU, Mel, DMF; v: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78°; then R1-X; vi: resolution (e.g. lipase); then isolation of methylester: DBU, Mel, DMF; vii: LiOHx1H20, MeOH, H20; viii:TFA,
CH2CI2; ix: FmocOSu, Na2C03aq., dioxane
A58: See C.-H. Lee, H. Kohn, J. Org. Chem. 1990, 55, 6098-6104 (R'=R8=H). A59: can be prepared according to Scheme 21.
Scheme 21
BocHN
i: NaOMe, MeOH; ii: NaH, THF; iii: NaOHaq., MeOH, 75°; then HCIaq.; iv: DBU, Mel, DMF; v: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78°; then R1-X; vi: resolution (e.g. lipase); then isolation of methylester: DBU, Mel, DMF; vii: LiOHx1 H20, MeOH, H20; viii:TFA,
CH2CI2; ix: FmocOSu, Na2C03aq., dioxane
A60: Compounds of this type can be prepared according to Scheme 22.
Scheme 22
i: NaH, DMSO; ii: NaOHaq., MeOH, 75°; then HCIaq.; iii: DBU, Mel, DMF; iv: NaOMe (2.2equiv.),
R -X; v. Raney-Ni, H2, EtOH; vi: CbzCI, Et3N, CH2CI2; vii: NaH, Br(CH2)2Br, THF; viii: resolution
(e.g. lipase); then DBU, Mel, DMF; ix: Pd/C, H2, EtOH; x: NaH, R^-X, THF; xi: LiOHx1 H20, MeOH, H20; xii: TFA, CH2CI2; xiii: FmocOSu, Na2C03aq., dioxane
A61: See D. R. Armour, K. M. Morriss, M. S. Congreve, A. B. Hawcock, Bioorg. Med. Chem. Lett. 1997, 7, 2037-2042 (R'=RI2=H).
A62: Compounds of this type can be prepared according to Scheme 23.
Scheme 23
i: resolution (e.g. lipase); then DBU, Mel, DMF; ii: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78°; then R6-X; iii: LiOHx1 H20, MeOH, H20; iv: TFA, CH2CI2; v: FmocOSu,
Na2C03aq., dioxane A63 See S E Gibson, N Guillo, R J Middleton, A Thuilliez, M J Tozer, J Chem Soc Perkin Trans 7, 1997, 4, 44 '-456, S E Gibson, N Guillo, S B Kalιndjan, M J Tozer, Bioorg Med
Chem Lett, 1997, 7, 1289-1292 (R'=H, R8= H), Beilstein Registry Number 459155 (R'=H, R8= 4,5-
Me02)
A64 Compounds of this type can be prepared according to Scheme 24 Scheme 24
BocHN
112 113 114
I NaH, DMSO, n Pd/C, H2, EtOH BuOCOCI, diisopropylethylamme, CH2CI2, then diazomethane, iv HBr, CH2CI2, v NaH, THF, vi NaOHaq , MeOH, 75°, then HCIaq , vn DBU, Mel,
DMF, VIII lithium diisopropylamide, THF, chlorotrimethylsilane, -78°, then R1-X, ix resolution
(e g lipase), then isolation of methylester DBU, Mel, DMF, x LιOHx1 H20, MeOH, H20, xi TFA,
CH2CI2, xii FmocOSu, Na2C03aq , dioxane
A65 and A 67 Compounds of these types can be prepared according to Schemes 25 and 26
Scheme 25
115 116 117
118 119 i: NaH, DMSO, BrCH(R1 )COOMe; ii: UOHx1 H20, MeOH, H20; iii: polyphosphoric acid; iv: NaH,
CICOOMe, THF; v: resolution (e.g. lipase); then isolation as methylester: DBU, Mel, DMF; vi:
LiOHx1 H20, MeOH, H20; vii: TFA, CH2CI2; viii: FmocOSu, Na2C03aq., dioxane
Scheme 26
123 124 125 i: NaH, THF, CH2I2; ii: NaH, DMSO; iii: Bu4NFx10H2O, THF; iv: methanesulfonylchloride, Et3N,
CH2CI2; then NaH, THF; v: NaOHaq., MeOH, 75°; then HCIaq.; vi: DBU, Mel, DMF; vii: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78°; then R -X; viii: Pd/C, H2, EtOH; ix: NaH,
THF, R14-X; x: resolution (e.g. lipase); then isolation of methylester: DBU, Mel, DMF; xi:
LiOHx1 H20, MeOH, H20; xii: TFA, CH2CI2; xiii: FmocOSu, Na2C03aq., dioxane A66 See G L Grunewald, L H Dahanukar, J Heterocycl Chem 1994, 31, 1609-1618 (R'=H , R8=H, 8-N02 , C(1)=0)
A68 See Gπesbeck , H Mauder, I Muller, Chem Ber 1992, 77, 2467-2476, (R'=R8=H, C(1)=0) A69 R Kreher, W Gerhardt, Liebigs Ann Chem 1981, 240-247 (R'=R8=H)
As explained above, building blocks A70 belong to the class of open-chain α-substituted α-amino acids, A71 and A72 to the class of the corresponding β-amino acid analogues and A73-A104 to the class of the cyclic analogues of A70
Building blocks of types A70 and A73-A104 have been synthesized by several different general methods by [2+2] cycloaddition of ketenes with imines (I Ojima, H J C Chen, X Quin, Tetrahedron Lett 1988, 44, 5307-5318), by asymmetric aldol reaction (Y Ito, M Sawamura, E Shirakawa, K Hayashikazi, T Hayashi, Tetrahedron Lett 1988, 29, 235-238, by the oxazolidmone method (J S Amato, L M Weinstock, S Karady, US 4508921 A, M Gander-Coquoz, D Seebach, Helv Chim Acta 1988, 77, 224-236, A K Beck, D Seebach, Chimia 1988, 42, 142-144, D Seebach, J D Aebi. M Gander-Coquoz, R Naef, He/v Chim Acta 1987, 70, 1194-1216, D Seebach, A Fadel. He/v Chim Acta 1995, 68, 1243-1250, J D Aebi, D Seebach, He7v Chim Acta 1985, 68, 1507-1518, A Fadel, J Salaun, Tetrahedron Lett 1987, 28, 2243-2246), by Schmidt- rearrangement ofα, -dιsubstιtuted α-ketoesters (G I Georg, X Guan, J Kant, Tetrahedron Lett 1988, 29, 403- 406), asymmetric synthesis via chiral Nι(II)- derived Schiff-bases (Y N Belokon, V I Bakhmutov, N I Chernoglazova, K A Kochetov, S V Vitt, N S Garbahnskaya, V M Behkov, J Chem Soc Perkin Trans 7, 1988, 305-312, M Kolb, J Barth, Liebigs Ann Chem 1983, 1668-1688), by the bis- lactim ether synthesis (U Schollkopf, R Ηmrichs, R Lonsky, Angew Chem 1987, 99, 137-138), by microbial resolution (K Sakashita, I Watanabe, JP 62/253397 A2) and by the hydantoin method combined with resolution of the racemic amino acids with chiral auxiliaries derived from L- phenylalanine amides (D Obrecht, C Spiegler, P Schonholzer, K Muller, Η Ηeimgartner, F Stierh, Helv Chim Acta 1992, 75, 1666-1696, D Obrecht, U Bohdal, J Daly, C Lehmann, P Schonholzer, K Muller, Tetrahedron 1995, 57, 10883-10900, D Obrecht, C Lehmann, C Ruffieux, P Schonholzer, K Muller, Helv Chim Acta 1995, 78, 1567-1587, D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 563-580, D Obrecht, Η Karajiannis, C Lehmann, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 703- 714, D Obrecht, M Altorfer, C Lehmann, P Schonholzer, K Muller, J Org Chem 1996, 67, 4080- 4086, D Obrecht, C Abrecht, M Altorfer, U Bohdal, A Gπeder, P Pfyffer, K Muller, Helv Chim Acta 1996, 79, 1315-1337) The latter method has been especially useful in preparing both enantiomers of building blocks of type A70 (see Scheme 27) and A73-A104 (see Scheme 28) in pure form Scheme 27
136a i KCN, (NH4)2C03, EtOH/H20, n Ba(OH)2, H20, in aq NaOH, PhCOCI, dioxane, then DCC,
CH2CI2, iv NaH, DMF, R 8-X or R19-X, v L-phenylalanine cyclohexylamide, N-methylpyrrolidone,
70°, vi CH3S03H, MeOH, 80°, vn 6N HCIaq , dioxane, 100°, vm Me3SιCI, DIEA, CH2CI2, then
FmocCI The method depicted in Scheme 27 consists in treatment of the appropriate ketones 126 with KCN, (NH4)2C03 m a mixture of ethanol/water (E Ware, J Chem Res 1950, 46, 403, L H Goodson, I L Homgberg, J j Lehmann, W H Burton, J Org Chem 1960, 25, 1920, S N Rastogi, J S Bmdra, N Anand, Ind J Chem 1971, 1175) to yield the corresponding hydantoms 127, which were hydrolyzed with Ba(OH)2 in water at 120-140° (R Sarges, R C Schur, J L Belletire, M J Paterson, J Med Chem 1988, 57, 230) to give 128 in high yields Schotten-Baumann acylation (Houben-Weyl, 'Methoden der Organischen Chemie', Volume XI/2, Stickstoff-Verbindungen II und III', Georg Tieme Verlag, Stuttgart, pp 339) followed by cyclization with N,N'-dιcyclohexyl carbodumide gave azlactones 129 (D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 563-580, D Obrecht, C Spiegler, P Schonholzer, K Muller, H Heimgartner, F Stierh, Helv Chim Acta 1992, 75, 1666-1696) Alternatively, azlactones 129 could also be prepared starting from amino acids 130 and 131, Schotten-Baumann acylation and cyclization with N,N'-dιcyclohexyl carbodumide to azlactones 132 and 133 and alkylation to yield 129 (D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 563-580, D Obrecht, C Spiegler, P Schonholzer, K Muller, H Heimgartner, F Stierh, Helv Chim Acta 1992, 75, 1666-1696)(see Scheme 1) Treatment of 129 with L-phenylalamne cyclohexylamide (D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 563-580) gave diastereomeric peptides 134 and 135, which could be conveniently separated by flash-chromatography or crystallisation Treatment of 134 and 135 with methanesulphonic acid in methanol at 80° gave esters 136a and 136b which were converted into the corresponding Fmoc-protected final building blocks 137a and 137b
Scheme 28
138 i: KCN, (NH4)2C03, EtOH/H20; ii: Ba(OH)2, H20; iii: aq.NaOH, PhCOCI, dioxane; then DCC,
CH2CI2; iv: L-phenylalanine cyclohexylamide, N-methylpyrrolidone, 70°; v: CH3S03H, MeOH,
80°; vi: 6N HCIaq., dioxane, 100°; vii: Me3SiCI, DIEA, CH2CI2; the FmocCI According to the general method described in Scheme 28 (D Obrecht, U Bohdal, C Broger, D Bur,
C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 563-580, D
Obrecht, C Spiegler, P Schonholzer, K Muller, H Heimgartner, F Stierh, Helv Chim Acta 1992,
75, 1666-1696) A73-A104 can be prepared starting from the corresponding ketones 138, hydantoin formation (139) (E Ware, J Chem Res 1950, 46, 403, L H Goodson, I L Honigberg, j j Lehmann, W H Burton, J Org Chem 1960, 25, 1920, S N Rastogi, J S Bindra, N Anand, Ind J Chem 1971, 1 175, D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, He7v Chim Acta 1995, 78, 563-580) and saponification (Ba(OΗ)2) to yield the racemic amino acids 140, which upon Schotten-Baumann-acylation and cyclization with N,N'- dicyclohexylcarbodiimide gave azlactones 141 Reaction with L-phenylalanme cyclohexylamide (D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 563-580) gave the diastereomeric peptides 142 and 143, which were separated by flash-chromatography or crystallization Treatment of 142 and 143 with methanesulphonic acid in methanol at 80° gave esters 144a and 144b which were converted into the corresponding suitably protected amino acid precursors 145a and 145b, ready for peptide synthesis
A71 Amino acid building blocks of this type (see formula 147) can be conveniently prepared from the corresponding disubstituted succinates 146 by C-.r- t.5-rearrangement as shown in Scheme 29 Scheme 29
HOOC
146 147 i diphenylphosphoryl azide, toluene, 80°, then benzyl alcohol
A71 See D Seebach, S Abele T Sifferlen, M Haenggi, S Gruner, P Seller, Helv Chim Acta 1998, 57, 2218-2243 (R18 and Rl9 form -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, R20=H), L Ducπe, S Re elt, P Seller, F Diedeπch, D R Bohn, R M Campbell, G L Olson, Helv Chim Acta 1999, 82, 2432-2447, C N C Drey, R J Ridge, J Chem Soc Perkin Trans 1, 1981, 2468-2471 , U P Dhokte, V V Khau, D R Hutchinson, M j Martinelh, Tetrahedron Lett 1998, 39, 8771 -8774 (RI8=RI9= Me, R20=H), D L Vane, D A Hay, S L Andis, T H Corbett, Bioorg Med Chem Lett 1999, 9, 369-374 (R18=RI9= Et), Testa, J Org Chem 1959, 24, 1928-1936 (Rl8= Et, Rl 9= Ph), M Haddad, C Wakselman, J Fluorine Chem 1995, 73, 57-60 (Rl8= Me, Rl9= CF3, R20=H), T Shono, K Tsubata, N Okmaga, J Org Chem 1984, 49, 1056-1059 (R18=Ri9=R20=Me), K Ikeda, Y Terao, M Sekiya, Chem Pharm Bull 1981, 29, 1747-1749 (R18 and R19 form -(CH2)5-, R20=Me) Amino acid building blocks of type A72 can be conveniently prepared by Arndt-Eistert Cl- homologation of compounds of type A70 according to Scheme 30
Scheme 30
148 149 i iBuOCOCI, dusopropylethylamine, CH2CI2, then diazomethane, hv or Cu(l)
A72 See Y V Zeιfman, J Gen Chem USSR (Engl Trans ) 1967, 37, 2355-2363 (RI8=R'9=CF3), W R Schoen, J M Pisano, K Pendergast, M J Wyvratt, M H Fisher, J Med Chem 1994, 37, 897- 906, S Thaisπvongs, D T Pals, D W DuCharme, S Turner, G L DeGraaf, J Med Chem 1991, 54, 655-642, T K Hansen, H Thoegersen, B S Hansen, Bioorg Med Chem Lett 1997, 7, 2951- 2954, R J DeVita, R Bochis, A J Frontier, A Kothar, M H Fisher, ./ Med Chem 1998, 41, 1716- 1728, D Seebach, P E Ciceπ, M Overhand, B Jaun, D Rigo, Helv Chim Acta 1996, 79, 2043- 2066, R P Nargund, K H Barakat, K Cheng, W Chan, B R Butler, A A Patchett, Bioorg Med Chem Lett 1996, 6, 1265-1270 (Rl =Rl9=Me), E Altmann, K Nebel, M Mutter, Helv Chim Acta 1991, 74, 800-806 (Rl8=Me, Rl9=COOMe)
A73 Compounds of this type can be prepared according to C Mapelh, G Tarocy, F Schwitzer, C H Stammer, -/ Org Chem 1989, 54, 145-149 (R2'= 4-OHC6H4), F Elrod, E M Holt, C Mapelh, C H Stammer, J Chem Soc Chem Commun 1988, 252-253 (R2'= CH2COOMe), R E Mitchell, M C Pirrung, G M McGeehan, Phytochemistry 1987, 26, 2695 (R2 I= CH2OH), j Bland, A Batolussi, C H Stammer, J Org Chem. 1988, 53, 992-995 (R2'= CH2NH2) Additional derivatives of A73 have been described by T Wakamiya, Y Oda, H Fujita, T Shiba, Tetrahedron Lett 1986, 27, 2143-2134, U Schollkopf, B Hupfeld, R Gull, Angew Chem 1986, 98, 755-756, J E Baldwin, R M Adlington, B j Rawhngs, Tetrahedron Lett 1985, 26, 481-484, D Kalvin, K Ramalinggam, R Woodard, Synth Comm 1985, 75, 267-272 and L M Izquierdo, I Arenal, M Bernabe, E Alvarez, Tetrahedron Lett 1985, 47, 215-220
A74 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding cyclobutanones
A75 and A76 Compounds of this type can be prepared using the following methods P Hughes, J Clardy, J Org Chem 1988, 53, 4793-4796, E A Bell, M Y Qureshi, R J Pryce, D H Janzen, P Lemke, J Clardy, J Am Chem Soc 1980, 702, 1409, Y Gaoni, Tetrahedron Lett 1988, 29, 1591- 1594, R D Allan, J R Haurahan, T W Hambley, G A R Johnston, K N Mewett, A D Mitrovic, J Med Chem 1990, 33, 2905-2915 (R23= COOH), G W Fleet, J A Seijas, M Vasquez Tato, Tetrahedron 1988, 44, 2077-2080 (R23= CH2OH)
A77 Compounds of this type can be prepared according to J H Burckhalter, G Schmied, J Pharm Sci 1966, 55, 443-445 (R23= aryl)
A78 Compounds of this type can be prepared according to J C Watkins, P Kroosgard-Larsen, T Honore, TIPS 1990, 77, 25-33, F Tπgalo, D Bπsson, R Azerad, Tetrahedron Lett 1988, 29, 6109 (R24= COOH)
A79 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding ρyrrohdιne-3-ones
A80-A82 Compounds of this type can be prepared according to D M Walker, E W Logusch, Tetrahedron Lett 1989, 30, 1181-1 184, Y Moπmoto, K Achiwa, Chem Pharm Bull 1989, 55, 3845-3849, J Yoshimura, S Kondo, M Ihara, H Hashimoto, Carbohydrate Res 1982, 99, 129-142
A83 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding pyrazohne-4-ones
A84 Compounds of this type can be prepared according to R M Pinder, B H Butcher, D H Buxton, D J Howells, J Med Chem 1971, 14, 892-893, D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 563-580
A85 Compounds of this type can be prepared according to general method described m Scheme 28 starting from the corresponding ιndane-l,3-dιones
A86 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding mdane-2-ones
A87 Compounds of this type and analogues thereof can be prepared according to C Cativiela, M D Diaz de Villegas, A Avenoza, J M Peregrina, Tetrahedron 1993, 47, 10987-10996, C Cativiela, P Lopez, J A Mayoral, Tetrahedron Assymmetry 1990, 1, 379, C Cativiela, J A Mayoral, A Avenoza, M Gonzalez, M A Rey, Synthesis 1990, 1114 A87 and A88 Compounds of this type can be prepared according to L Munday, J Chem Soc 1961, 4372, J Ansell, D Morgan, H C Price, Tetrahedron Lett 1978, 47, 4615-4616
A89 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding pιpeπdιne-3-ones
A90 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding tetrahydrothιapyran-3-ones
A91 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding tetrahydropyran-3-ones
A92 Compounds of this type can be prepared according to general method described m Scheme 28 starting from the corresponding pιpeπdιne-2,5-dιones
A93 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding cyclohexanones
A94 Compounds of this type can be prepared according to J Org Chem 1990, 55, 4208
A95 Compounds of this type can be prepared according to N J Lewis, R L Inloes, J Hes, R H Matthews, G Mύo, J Med Chem 1978, 27, 1070-1073
A96 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding tetrahydropyran-4-ones
A97 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding pιpeπdιne-2,4-dιones
A98 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding 1-tetralones (D Obrecht, C Spiegler, P Schonholzer, K Muller, H Heimgartner, F Stierh, Helv Chim Acta 1992, 75, 1666-1696)
A99 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding tetrahne- 1 ,4-dιone mono-diethylacetals A100 Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding tetrahydroquιnolm-4-ones
AlOl Compounds of this type can be prepared according to general method described in Scheme 28 starting from the corresponding tetrahydroquιnohne-2,4-dιones
A102 Compounds of this type can be prepared according to K Ishizumi, N Ohashi, N Tanno, J Org Chem 1987, 52, 4477-4485, D Obrecht, U Bohdal, C Broger, D Bur, C Lehmann, R Ruffieux, P Schonholzer, C Spiegler, Helv Chim Acta 1995, 78, 563-580, D Obrecht, C Spiegler, P Schonholzer, K Muller, H Heimgartner, F Stierh, Helv Chim Acta 1992, 75, 1666-1696, D R Hames, R W Fuller, S Ahmad, D T Vistica, V E Marquez, J Med Chem 1987, 30, 542-547, T Decks, P A Crooks, R D Waigh, J Pharm Sci 1984, 73, 457-460, 1 A Blair, L N Mander, Austr J Chem 1979, 32, 1055-1065
Overviews dealing with building blocks of types (b)-(p) are S Hanessian, G McNaughton-Smith, H -G Lombart, W D Lubell, Tetrahedron 1997, 38, 12789-12854, D Obrecht, M Altorfer, J A Robinson, "Novel Peptide Mimetic Building Blocks and Strategies for Efficient Lead Finding", Adv Med Chem 1999, Vol 4, 1-68
Templates of type (bl) can be prepared according to Schemes 31 and 32
Scheme 31
153 154
l Treatment of 150 with a dehydrating reagent such as thionylchlonde in methanol at an elevated temperature, conveniently at reflux 11 Introduction of Boc, e g using di-tert -butyl dicarbonate and triethylamine in a suitable solvent such as dichloromethane, any other suitable N-protecting group (not shown in Reaction
Scheme 31) can be introduced in an analogous manner in Reaction of formed product with phthalimide, diethyl diazodicarboxylate and tπphenylphoshine under standard Mitsunobu conditions (Mitsunobu, O , Wada, M , Sano, T
J J Am Chem Soc 1972, 94, 672) to conveniently yield 151 iv Treatment of 151 with tπfluoracetic acid in dichloromethane v 152 is coupled under standard peptide coupling conditions with Cbz-Asρ(tBu)OH in DMF with reagents such as HBTU and 1-hydroxybenztπazole (HOBt) with a base such as diisopropylethylamine to yield 153 vi Removal of the Cbz-group, conveniently by hydrogenation using H and a catalyst such as
Palladium on charcoal, in solvents such as ethanol, DMF and ethyl acetate vn The phthalimide group is cleaved off from the resulting product, conveniently by treatment with hydrazine in a suitable solvent such as ethanol at an elevated temperature, suitably at about 80° C and cleavage of the formed product with tnfluoracetic acid in CH2C12 vin The formed amino acid is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine m a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 154 as described by Bisang, C , Weber, C , Robinson, J A He7v Chim Acta 1996, 79, 1825-1842
Scheme 32
159 l Treatment of 150 with a dehydrating reagent such as thionyl chloride in a suitable solvent such as methanol at an elevated temperature, conveniently at reflux ii The resulting amino acid ester is N-protected under standard conditions for introducing the
Cbz-group, e g using benzyloxycarbonyl chloride and triethylamine in a suitable solvent such as dichloromethane in The Cbz-protected amino acid methyl ester is treated with tπmethylsilylchloπde and a base such as triethylamine in a solvent such as tetrahydrofuran, cooled, conveniently to about -78°
C, followed by reaction with a strong base such as lithium dnsopropylamide or lithium hexamethyldisilylazide and tert -butyl bromoacetate yielding 155 as a mixture of diastereomers as described by Bisang, C , Jiang, L , Freund, E , Emery, F , Bauch, C , Matile, H„ Pluschke, G , Robinson, J A J Am Chem Soc 1998, 720, 7439-7449, Emery, F , Bisang, C , Favre, M , Jiang, L , Robinson, J A J Chem Soc Chem Commun 1996, 2155-
2156 iv Reaction of 155 with phthalimide, diethyl diazodicarboxylate and tπphenylphosphine under standard Mitsunobu conditions (Mitsunobu, O , Wada, M , Sano, T J J Am Chem Soc 1972 94, 672) v The resulting product is hydrogenated using H2 and a suitable catalyst such as palladium on charcoal in a solvent such as ethyl acetate, DMF or ethanol, subsequently separation of diastereomers takes place and yields 156 vi 156 is coupled with Fmoc-Asp(allyl)OH under standard peptide coupling conditions using reagents such as HATU, HOAt and a base such as diisopropylethylamme in a suitable solvent such as DMF vn Cyclization, conveniently with DBU in DMF to yield 157 viu The phthalimide group is cleaved off from resulting product, conveniently by hydrazmolysis, e g treatment with methylhydrazine in a suitable solvent such as DMF ix The formed product is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succinimide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 158 x Standard removal of an allyl ester group using e g palladιum(O) as catalyst gives 159
Templates of type (b2) can be prepared according to Scheme 33 Scheme 33
Vitamin C Me
160 161
tBu
162 163
XI.XII
164
160 (obtainable from Vitamin C as described by Hubschwerlen, C. (Synthesis 1986, 962) is treated with phthalimide, diethyl diazodicarboxylate and tnphenylphoshine under standard
Mitsunobu conditions (Mitsunobu, O.; Wada, M.; Sano, T. J. J. Am. Chem Soc. 1972, 94,
672). n: The phthalimide group is cleaved off from the product, conveniently by hydrazmolysis, e.g. by treatment with methylhydrazine in a suitable solvent such as DMF nr The amino group is protected by treatment with a benzoylatmg reagent such as benzoic acid anhydride or benzoylchloπde and a base such as triethylamine or
4-dιmethylamιnopyπdιne in a suitable solvent such as dichloromethane or DMF iv Removal of the 2,4-dιmethoxybenzyl group, e g with K2S208 and Na2HP0 in aqueous acetonitrile at an elevated temperature, e g at about 80° C v. Introduction of a tert -butoxycarbonyl group using e g di-tert -butyloxycarbonyl dicarbonate, triethylamine and a catalytic amount of 4-dιmethylamιnopyπdιne in a suitable solvent such as dichloromethane vi : Reaction with aqueous sodium carbonate in tetrahydrofuran followed by acidification vu Esteπfication of the carboxylic acid group, conveniently with diazomethane in a suitable solvent such as diethylether yielding 161 viu Removal of the Cbz-group, conveniently by hydrogenation with H2 in the presence of a catalyst such as palladium on charcoal in a solvent such as DMF to yield 161 as described by Pfeifer, M , Robinson, J A J Chem Soc Chem Commun 1998, 1977 ix 161 is coupled under standard peptide coupling conditions with Cbz-Asp(tBu)OH in DMF with reagents such as HBTU and 1 -hydroxybenztπazole with a base such as dnsopropylethylamine to yield 162 as described by Pfeifer, M , Robinson, J A J Chem Soc Chem Commun 1998, 1977 x Removal of the Cbz-group, e g by hydrogenation using H2 and a catalyst such as palladium on charcoal under standard conditions, yields 163 as described by Pfeifer, M , Robinson, J A J Chem Soc Chem Commun 1998, 1977 xi Cleavage of the tert -butyl ester and tert -butyloxycarbonyl groups, conveniently using tπfluoracetic acid in dichloromethane or 4N hydrochloric acid in dioxane xii The intermediate free amino acid formed is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 164 as described by Pfeifer, M , Robinson, J A J Chem Soc Chem Commun 1998, 1977
Templates of type (cl) can be prepared according to Schemes 34 to 37
Scheme 34
Vll-X
i 166 can be synthesized from 165 according to P Waldmeier, "Solid-supported synthesis of highly substituted xanthene-deπved templates for the synthesis of β-tum stabilized cyclic peptide libraries", PhD-thesis, University of Zurich, 1996 For cleaving the phthalimide group 166 is conveniently submitted to hydrazmolysis, e g by treatment with hydrazine hydrate in a suitable solvent such as ethanol at an elevated temperature, e g at about 80° C n The intermediate aminonitπle is saponified, conveniently under basic conditions, e g with aqueous sodium hydroxide in a suitable solvent such as ethanol at an elevated temperature, conveniently under reflux, to yield 167
HI The intermediate free amino acid formed is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succinimide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 168 as described by P Waldmeier, "Solid- supported synthesis of highly substituted xanthene-deπved templates for the synthesis of β- turn stabilized cyclic peptide libraries", PhD-thesis, University of Zurich, 1996 iv Regioselective bromination of 167 is performed preferably with bromine in acetic acid and dichloromethane In a similar fashion R37 = N02 can be introduced by treatment with HN03 in acetic acid and R37 = CH2-NPht by treatment with hydroxymethyl phthalimide in H2S04 v The amino group is conveniently Cbz-protected with reagents such as benzyloxycarbonyl chloride or succimmide in a suitable solvent such as dioxane in presence of a base such as aqueous sodium hydroxide vi The carboxylic acid group is esteπfied, preferably with DBU and methyl iodide in DMF to yield 169 vii Introduction of lower alkyl, substituted lower alkyl and aryl substituents (R37), conveniently by palladιum(O)- catalyzed Stille- (Stille, J K Angew Chem 1986, 68, 504) and Suzuki- couplmgs (Oh-e, T , My aura, N , Suzuki, A J Org Chem 1993, 58, 2201) Any other functionahzation known for aryl bromides can be employed for introduction of substituents R37 via Removal of the Cbz-group, e g by hydrogenation using H2 and a catalyst such as palladium on charcoal in a suitable solvent such as ethanol, DMF and ethyl acetate ix Hydrolysis of the ester group, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, preferably at about 100° C x The intennediate free amino acid formed is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 170
Scheme 35
iv (R37=R38)
Double ortho- brommation of 171 is performed preferably with excess bromine in acetic acid and dichloromethane In a similar fashion R37 = R38 = N02 can be introduced by treatment with HN03 in acetic acid and R37 = R38 = CH2-NPht by treatment with hydroxymethyl phthalimide in H2S0
The amino group is protected, conveniently Cbz-protected, with reagents such as benzyloxycarbonyl chloride or succimmide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide
111 The carboxylic acid group is esteπfied, preferably with DBU and methyl iodide in DMF to yield 172
IV Introduction of lower alkyl, substituted lower alkyl and aryl substituents (R37 = R38), e g by palladιum(O)- catalyzed Stille- (Stille, J K Angew Chem 1986, 68, 504) and Suzuki- couplmgs (Oh-e, T , M aura, N , Suzuki, A J Org Chem 1993, 58, 2201) Any other ftinctionalization known for aryl bromides can be employed for introduction of substituents
R37 and R38
Removal of the Cbz-group of 173, e g by hydrogenation using H2 and a catalyst such as palladium on charcoal in a suitable solvent such as ethanol, DMF or ethyl acetate
VI Hydrolysis of the ester group, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, conveniently at about 100° C vπ The intermediate free amino acid formed is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 174. Scheme 36
Vlll-X
l Cleavage of the methoxy groups of 166, preferably by treatment with an excess of boron tnbromide in a suitable solvent such as dichloromethane ii Hydrolysis of the cyano group under acidic conditions, preferably with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, conveniently at about 100° C in The resulting acid is treated with a dehydrating agent such as thionyl chloride in a suitable solvent such as dioxane to yield 175 iv Treatment of 175 with an appropriate tπflating reagent, preferably trifluoromethanesulfonic acid anhydride in the presence of a base such as 2,6-dι-tert -butyl-pyridine m a suitable solvent such as dichloromethane v Heating of the intermediate, conveniently in a suitable solvent such as methanol
VI Introduction of lower alkyl or aryl-lower alkyl (R35) by alkylation to yield 177 Any other functionahzation known for phenol groups can be employed for introduction of substituents
R35 vπ Introduction of lower alkyl or aryl (R3δ), conveniently by palladιum(O)- catalyzed Suzuki- couphng (Oh-e, T , Myaura, N , Suzuki, A J Org Chem 1993, 58, 2201) to yield 178 Any other functionahzation known for aryl bromides can be employed for introduction of substituents
R36 vui Hydrolysis of the ester group under acidic conditions, conveniently with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, e g at about 100° C ix Cleavage of the phthahmido group, conveniently by hydrazmolysis, e g with hydrazine hydrate in a suitable solvent such as ethanol x The intennediate free amino acid formed is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 179. Scheme 37
l Brommation of 175 using reagents such as bromine in a mixture of acetic acid and dichloromethane at temperatures ranging from about 0° C to about room temperature u Benzoylation of the hydroxy group using an appropriate acylating agent such as benzoyl chloride or benzoic acid anhydride, a base such as pyridine or triethylamine and a suitable solvent such as dichloromethane to yield 180 in 180 is treated with methanol and a catalytic amount of an acidic catalyst such as camphor sulfomc acid under heating iv Introduction of lower alkyl or aryl-lower alkyl (R35) by alkylation using a base such as sodium hydride or potassium tert -butoxide m a solvent such as tetrahydrofuran, dimethoxyethane or
DMF gives 181 v Lower alkyl, substituted lower alkyl and aryl substituents (R38) are introduced, e g by palladιum(O)- catalyzed Stille- (Stille, J K Angew Chem 1986, 68, 504) and Suzuki- couplmgs (Oh-e, T , Myaura, N , Suzuki, A J Org Chem 1993, 58, 2201) Any other functionahzation known for aryl bromides can be employed for introduction of substituents
R38 vi For cleaving the benzyloxy group the intermediate is conveniently heated with sodium cyanide adsorbed on aluminum oxide and methanol vii Treatment with an appropriate tπflating reagent, preferably trifluoromethanesulfonic acid anhydride, in the presence of a base such as 2,6-dι-tert -butyl-pyndine in a suitable solvent such as dichloromethane via Introduction of lower alkyl and aryl substituents (R36), e g by palladιum(O)- catalyzed Stille- (Stille, J K Angew Chem 1986, 68, 504) and Suzuki- couplings (Oh-e, T , Myaura, N ,
Suzuki, A J Org Chem 1993, 58, 2201) yields 182 Any other functionahzation known for aryl bromides can be employed for introduction of substituents R36 ix Brommation under standard conditions such as using bromine m acetic acid and dichloromethane at temperatures ranging from about 0° C to about room temperature x Lower alkyl, substituted lower alkyl and aryl substituents (R37) are introduced, e g by palladιum(O)- catalyzed Stille- (Stille, J K Angew Chem 1986, 68, 504) and Suzuki- couphngs (Oh-e, T , Myaura, N , Suzuki, A J Org Chem 1993, 58, 2201) to yield 184 Any other functionahzation known for aryl bromides can be employed for introduction of substituents R37 xi The ester group is hydrolyzed under acidic conditions, conveniently with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, e g at about 100° C xu The phthahmido group is cleaved, e g by hydrazmolysis, conveniently with hydrazine hydrate in a suitable solvent such as ethanol xui The intermediate free amino acid formed is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 185
Templates of type (c2) can be prepared as shown in Schemes 38 and 39 Scheme 38
V-VII
V-VII
3,7-Dimethoxyphenothiazine 186 is prepared and converted into 187 according to Muller, K.; Obrecht, D.; Knierzinger, A.; Spiegler, C; Bannwarth, W.; Trzeciak, A.; Englert, G.; Labhardt, A.; Schonholzer, P. Perspectives in Medicinal Chemistry, Editor Testa, B.; Kyburz, E.; Fuhrer, W.; Giger, R., Weinheim, New York, Basel, Cambridge: Verlag Helvetica Chimica Acta, 1993, 513-531; Bannwarth, W.; Gerber, F.; Grieder, A.; Knierzinger, A.; Muller, K.; Obrecht. D.; Trzeciak, A. Can. Pat. Appl. CA2101599(131 pages). The benzyl group is cleaved off from 187 conveniently by hydrogenation, e.g. with H2 and a catalyst such as palladium on charcoal in a suitable solvent such as ethanol, DMF or ethyl acetate. Introduction of lower alkyl (R43) by alkylation using an appropriate alkylating agent (R 3-X'; X - OTf, Br, I) and strong bases such as sodium amide in liquid ammonia or sodium hydride in tetrahydrofuran, dioxan or DMF in the presence of a phase transfer catalyst such as TDA-I. In a similar manner substituted lower alkyl (R43) can be introduced; thus, for example R43 = CH2COOR55 and CH CH2COOR55 can be introduced by treatment with the appropriate 2-halo acetic and, respectively, 3-halo propionic acid derivatives. Any other functionahzation known for diarylamines can be employed for introduction of substituents R43. in Cleavage of the methoxy groups of 188, conveniently by treatment with an excess of boron tnbromide in a suitable solvent such as dichloromethane at temperatures ranging from about -20° C to about room temperature iv For the introduction of lower alkyl, substituted lower alkyl or aryl-lower alkyl substituents (R39 and R40) the intermediate bis-phenol derivative is conveniently reacted with a reagent of the formula R39-and R40-X' (X' = OTf, Br, I) in the presence of strong bases such as sodium hydride in tetrahydrofuran, dioxan or DMF in the presence of a phase transfer catalyst such as TDA-I Any other functionahzation known for phenol groups can be employed for introduction of substituents R39 and R40
The cyano group of 188 and, respectively, 189 is hydrolyzed, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, e g at about 100° C vi The phthalimide group of the intermediate is cleaved, conveniently by hydrazmolysis, e g with hydrazine hydrate in a suitable solvent such as ethanol vii The free ammo group is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 190 and, respectively, 191 Scheme 39
IX-XII
IX-XII
l The cyano group of 188 is hydrolyzed, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, e g at about 100° C ii The phthalimide group of the intermediate is cleaved, conveniently by hydrazmolysis, e g with hydrazine hydrate m a suitable solvent such as ethanol to yield 192 m Double ortho- brommation of 192 is performed preferably with excess bromine in acetic acid and dichloromethane In a similar fashion R4' = R42 = N02 can be introduced by treatment with HN03 m acetic acid and R41 = R42 = CH2-NPht by treatment with hydroxymethyl phthalimide in H2S0 Any other functionahzation by electrophilic aromatic substitution known can be employed for introduction of substituents R ' and R42 iv The amino group is protected, conveniently Cbz-protected, with reagents such as benzyloxycarbonyl chloride or succimmide m a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide v The carboxylic acid group is esterified, preferably with DBU and methyl iodide in DMF to yield 193 vi Regioselective brommation of 192 is performed preferably with bromine in acetic acid and dichloromethane In a similar fashion R4' = N02 can be introduced by treatment with HNO3 in acetic acid and R41 = CH2-NPt by treatment with hydroxymethyl phthalimide in H2S04 Any other functionahzation by electrophilic aromatic substitution known can be employed for introduction of substituents R4 ' vii The amino group is conveniently Cbz-protected with reagents such as benzyloxycarbonyl chloride or succimmide in a suitable solvent such as dioxane in presence of a base such as aqueous sodium hydroxide viu The carboxylic acid group is esterified, preferably with DBU and methyl iodide in DMF to yield 194 ix Introduction of lower alkyl, substituted lower alkyl and aryl substituents (R ')for 194 and (R41 and R42) for 193, conveniently by palladιum(O)- catalyzed Stille- (Stille, J K Angew Chem 1986, 68, 504) and Suzuki- couplings (Oh-e, T , Myaura, N , Suzuki, A J Org Chem 1993, 58, 2201) Any other functionahzation known for aryl bromides can be employed for introduction of substituents R4' and R42 x Removal of the Cbz-group, e g by hydrogenation using H2 and a catalyst such as palladium on charcoal in a suitable solvent such as ethanol, DMF and ethyl acetate xi Hydrolysis of the ester group, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, preferably at about 100° C xn The intermediate free amino acid formed is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 195 and 196
Templates of type (c3) can be prepared as shown in Schemes 40 and 47
Scheme 40
Resorufin
V-VII
197 can be prepared from commercial resorufin and coverted into 198 according to Muller, K , Obrecht, D , Knierzinger, A , Spiegler, C , Bannwarth, W , Trzeciak, A , Englert, G , Labhardt, A , Schonholzer, P Perspectives in Medicinal Chemistry, Editor Testa, B , Kyburz, E , Fuhrer, W , Giger, R , Weinheim, New York, Basel, Cambridge Verlag Helvetica Chimica Acta, 1993, 513-531, Bannwarth, W , Gerber, F , Gπeder, A , Knierzinger, A , Muller, K , Obrecht D , Trzeciak, A Can Pat Appl CA2101599(131 pages) For splitting off the benzyl group 198 is conveniently hydrogenated e g with H2 and a catalyst such as palladium on charcoal in a suitable solvent such as ethanol, DMF or ethyl acetate n Introduction of lower alkyl (R41) by alkylation with R43-X' (X' = OTf, Br, I) using strong bases such as sodium amide in liquid ammonia or sodium hydride in tetrahydrofuran, dioxan or DMF in the presence of a phase transfer catalyst such as TDA-I to yield 199 In a similar manner substituted lower alkyl (R43) can be introduced; thus, for example, R43 = CH2COOR55 and CH2CH2COOR5S can be introduced by treatment with the appropriate 2-halo acetic and, respectively, 3-halo propionic acid derivatives. Any other functionahzation of diarylamino groups known can be employed for introduction of substituents R43 in Cleavage of the methoxy groups of 199, conveniently by treatment with excess boron tnbromide in dichloromethane at temperatures ranging from about -20° to about room temperature iv The intermediate bis-phenol derivative is preferably reacted with R39 and R 0-X' (X - OTf, Br,
I) in the presence of strong bases such as sodium hydride in tetrahydrofuran, dioxan or DMF in the presence of a phase transfer catalyst such as TDA-I Any other functionahzation for phenol groups can be employed for introduction of substituents R39 and R40 v The cyano group of 199 and, respectively, 200 is hydrolyzed under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, conveniently at about 100° C vi- The phthalimide group is cleaved, conveniently by hydrazmolysis, e g with hydrazine hydrate in suitable solvent such as ethanol vπ. The free amino group is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 201 and, respectively, 202
Scheme 41
IX-XII
IX-XII
l The cyano group of 199 is hydrolyzed, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, e g at about 100° C ii The phthalimide group of the intermediate is cleaved, conveniently by hydrazmolysis, e g with hydrazine hydrate in a suitable solvent such as ethanol to yield 203 m Double ortho- brommation of 203 is performed preferably with excess bromine in acetic acid and dichloromethane In a similar fashion R4' = R42 = N02 can be introduced by treatment with HN03 in acetic acid and R41 = R42 = CH2-NPht by treatment with hydroxymethyl phthalimide in H2S04 Any other functionahzation by electrophilic aromatic substitution can be employed for introduction of substituents R4' and R42 iv The amino group is protected, conveniently Cbz-protected, with reagents such as benzyloxycarbonyl chloride or succimmide in a suitable solvent such as dioxane m the presence of a base such as aqueous sodium hydroxide v The carboxylic acid group is esterified, preferably with DBU and methyl iodide in DMF to yield 204 vi Regioselective brommation of 203 is performed preferably with bromine in acetic acid and dichloromethane In a similar fashion R4' = N02 can be introduced by treatment with HN0 in acetic acid and R4'=CH2-NPht by treatment with hydroxymethyl phthalimide in H2S0 ii The amino group is conveniently Cbz-protected with reagents such as benzyloxycarbonyl chloride or succimmide in a suitable solvent such as dioxane in presence of a base such as aqueous sodium hydroxide viu The carboxylic acid group is esterified, preferably with DBU and methyl iodide in DMF to yield 205 ix Introduction of lower alkyl, substituted lower alkyl and aryl substituents (R4i)f°r 205 and (R41 and R42) for 204, conveniently by ρalladιum(O)- catalyzed Stille- (Stille, J K Angew
Chem 1986, 68, 504) and Suzuki- couplings (Oh-e, T , Myaura, N , Suzuki, A J Org Chem 1993, 58, 2201) Any other functionahzation known for aryl bromides can be employed for introduction of substituents R41 and R42 x Removal of the Cbz-group, e g by hydrogenation using H2 and a catalyst such as palladium on charcoal in a suitable solvent such as ethanol, DMF and ethyl acetate xi Hydrolysis of the ester group, conveniently under acidic conditions, e g with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at an elevated temperature, preferably at about 100° C xii The intermediate free amino acid formed is conveniently protected with reagents such as 9- fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl succimmide using a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to yield 206 and 207
Templates(d) can be prepared according to D Obrecht, U Bohdal, C Lehmann, P Schonholzer, K Muller, Tetrahedron 1995, 57, 10883, D Obrecht, C Abrecht, M Altorfer, U Bohdal, A Gneder, M Kleber. P Pfyffer, K Muller, Helv Chim Acta 1996, 79, 1315-1337
Templates (el) and (e2) See R Mueller, L Revesz, Tetrahedron Lett 1994, 35, 4091, H -G Lubell, W D Lubell, J Org Chem 1996, 61, 9437, L Colombo, M DiGiacomo, G Papeo, O Carugo, C Scolastico, L Manzoni, Tetrahedron Lett 1994, 35, 4031
Templates (e3) See S Hanessian, B Ronan, A Laoui, Bioorg Med Chem Lett 1994, 4, 1397
Templates (e4) See S Hanessian, G McNaughton-Smith, Bi oorg Med Chem Lett 1996, (5, 1567
Templates (I) See T P Cuπan, P M McEnay, Tetrahedron Lett 1995, 36, 191-194 Templates (g) See D Gramberg, C Weber, R Beeh, J Inglis, C Bruns, J A Robinson, Helv Chem Acta 1995, 78, 1588-1606, K H Kim, J P Dumas, J P Germanas, J Org Chem 1996, 61, 3138-3144
Templates (h) See S de Lombart, L Blanchard, L B Stamford, D M Sperbeck, M D Grim, T M Jenson, H R Rodriguez, Tetrahedron Lett 1994, 35, 7513-7516
Templates (il) See J A Robl, D S Karanewski, M M Asaad, Tetrahedron Lett 1995, 5, 773-758
Templates (i2) See T P Burkholder, T -B Le, E L Giroux, G A Flynn, Bioorg Med Chem Lett 1992, 2, 579
Templates (i3) and (i4) See L M Simpkins, J A Robl, M P Cimarusti, D E Ryono, J Stevenson, C -Q Sun, E W Petπllo, D S Karanewski, M M Asaad, J E Bird, T R Schaeffer, N C Tnppodo, Abstracts of papers, 210th Am Chem Soc Meeting, Chicago, 111, MEDI 064 (1995)
Templates (k) See D Benlshai, A R McMurray, Tetrahedron 1993, 49, 6399
Templates (1) See E G von Roedern, H Kessler, Angew Chem Int Ed Engl 1994, 33, 687-689
Templates (m) See R Gonzalez-Mumz, M J Dominguez, M T Garcia-Lopez, Tetrahedron 1992, 45, 5191-5198
Templates (n) See F Esser, A Carpy, H Bnem, H Koppen, K -H Pook, Int J Pept Res 1995, 45, 540-546
Templates (o) See N De la Figuera, I Alkorta, T Garcia-Lopez, R Herranz, R Gonzalez-Mumz, Tetrahedron 1995, 57, 7841
Templates (p) See U Slomcynska, D K Chalmers, F Cornille, M L Smythe, D D Benson, K D Moeller. G R Marshall, J Org Chem 1996, 61, 1198-1204
The β-hairpin peptidomimetics of the invention can be used in a wide range of applications in order to inhibit the growth of or to kill microorganisms In particular they can be used to selectively inhibit the growth of or to kill microorganisms such as Pseudomonas aeruginosa and Acinetobacter They can be used for example as disinfectants or as preservatives for materials such as foodstuffs, cosmetics, medicaments and other nutnent-containing materials The β-hairpin peptidomimetics of the invention can also be used to treat or prevent diseases related to microbial infection m plants and animals
For use as disinfectants or preservatives the β-hairpm peptidomimetics can be added to the desired material singly, as mixtures of several β-hairpin peptidomimetics or in combination with other antimicrobial agents The β-hairpm peptidomimetics may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well known in the art
When used to treat or prevent infections or diseases related to such infections, particularly infections related to respiratory diseases such as cystic fibrosis, emphysema and asthma, infections related to skin or soft tissue diseases such as surgical wounds, traumatic wounds and burn wounds, infections related to gastrointestinal diseases such as epidemic diarrhea, necrotizing enterocohtis and typhlitis, infections related to eye diseases such as keratitis and endophthalmitis, infections related to ear diseases such as otitis, infections related to CNS diseases such as brain abscess and meningitis, infections related to bone diseases such as osteochondπtis and osteomyelitis, infections related to cardiovascular diseases such as endocartitis and pericarditis, infections related to gastrouπnal diseases such as epididymitis, prostatitis and urethntis, the β-hairpin peptidomimetics can be administered singly, as mixtures of several β-hairpin peptidomimetics, in combination with other antimicrobial or antibiotic agents, or anti cancer agents, or antiviral (e g anti-HIV) agents, or in combination with other pharmaceutically active agents The β-hairpin peptidomimetics can be administered per se or as pharmaceutical compositions
Pharmaceutical compositions comprising β-hairpin peptidomimetics of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophihzing processes Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active β- hairpin peptidomimetics into preparations which can be used pharmaceutically Proper formulation depends upon the method of administration chosen
For topical administration the β-hairpin peptidomimetics of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc as are well-known in the art Systemic formulations include those designed for administration by injection, e g subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration
For injections, the β-hairpin peptidomimetics of the invention may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hink's solution, Ringer's solution, or physiological saline buffer The solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents Alternatively, the β-hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e g , sterile pyrogen-free water, before use
For transmucosal administration, penetrants appropnate to the barrier to be permeated are used in the formulation as known in the art
For oral administration, the compounds can be readily formulated by combining the active β-hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art Such carriers enable the β-hairpin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurnes, suspensions etc , for oral ingestion of a patient to be treated For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol, cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrohdone (PVP), granulating agents, and binding agents If desired, desintegratmg agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques
For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable earners, excipients or diluents include water, glycols, oils, alcohols, etc In addition, flavoring agents, preservatives, coloring agents and the like may be added
For buccal administration, the composition may take the form of tablets, lozenges, etc formulated as usual
For administration by inhalation, the β-hairpin peptidomimetics of the invention are conveniently delivered in form of an aeorosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e g dichlorodifluoromethane, tπchlorofluromethane, carbon dioxide or another suitable gas In the case of a pressunzed aerosol the dose unit may be determined by providing a valve to deliver a metered amount Capsules and cartridges of e g gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the β-hairpin peptidomimetics of the invention and a suitable powder base such as lactose or starch
The compounds may also be formulated in rectal or vaginal compositions such as suppositones together with appropriate suppository bases such as cocoa butter or other glyceπdes
In addition to the formulations described previously, the β-hairpin peptidomimetics of the invention may also be formulated as depot preparations Such long acting formulations may be administered by implantation (e g subcutaneously or intramuscularly) or by intramuscular injection For the manufacture of such depot preparations the β-hairpin peptidomimetics of the invention may be formulated with suitable polymeric or hydrophobic materials (e g as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts
In addition, other pharmaceutical delivery systems may be employed such as liposomes and emulsions well known in the art Certain organic solvents such as dimethylsulfoxide also may be employed Additionally, the β-hairpin peptidomimetics of the invention may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent Various sustamed-release materials have been established and are well known by those skilled m the art Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed
As the β-hairpm pepdidomimetics of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as pharmaceutically acceptable salts Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than are the corresponding free base forms
The β-hairpm peptidomimetics of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose It is to be understood that the amount used will depend on a particular application For example, for use as a desinfectant or preservative, an antimicrobially effective amount of a β- hairpin peptidomimetic of the invention, or a composition thereof, is applied or added to the material to be desinfected or preserved By antimicrobially effective amount is meant an amount of a β-hanpin peptidomimetic of the invention or composition that inhibits the growth of, or is lethal to, a target microbe population While the antimicrobially effective amount will depend on a particular application, for use as desmfectants or preservatives the β-hairpm peptidomimetics of the invention, or compositions thereof, are usually added or applied to the material to be desinfected or preserved m relatively low amounts Typically, the β-hairpin peptidomimetics of the invention comprise less than about 5% by weight of a desinfectant solution or material to be preserved, preferably less than 1% by weight and more preferably less than 0 1% by weight An ordinary skilled expert will be able to determine antimicrobially effective amounts of particular β-hairpm pepdidomimetics of the invention for particular applications without undue experimentation using, for example, the in vitro assays provided in the examples
For use to treat or prevent microbial infections or diseases related to such infections, the β-hairpm pepidomimetics of the invention, or compositions thereof, are administered or applied in a therapeutically effective amount By therapeutically effective amount is meant an amount effective m ameliorating the symptoms of, or in ameliorating, treating or preventing microbial infections or diseases related thereto Determination of a therapeutically effective amount is well within the capacities of those skilled in the art, especially in view of the detailed disclosure provided herein
As in the case of desmfectants and preservatives, for topical administration to treat or prevent bacterial infections a therapeutically effective dose can be determined using, for example, the in vitro assays provided in the examples The treatment may be applied while the infection is visible, or even when it is not visible An ordinary skilled expert will be able to determine therapeutically effective amounts to treat topical infections without undue experimentation
For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays For example, a dose can be formulated in animal models to achieve a circulating β-hairpin peptidomimetic concentration range that includes the IC50 as determined in the cell culture (I e the concentration of a test compound that is lethal to 50% of a cell culture), the MIC, as determined in cell culture (l e the concentration of a test compound that is lethal to 100% of a cell culture) Such information can be used to more accurately determine useful doses in humans Initial dosages can also be determined from in vivo data, e g animal models, using techniques that are well known in the art One having ordinary skills in the art could readily optimize administration to humans based on animal data
Dosage amount for applications as antimicrobial agents may be adjusted individually to provide plasma levels of the β-hairpm peptidomimetics of the invention which are sufficient to maintain the therapeutic effect Therapeutically effective serum levels may be achieved by administering multiple doses each day
In cases of local administration or selective uptake, the effective local concentration of the β-hairpin peptidomimetics of the invention may not be related to plasma concentration One having the skills in the art will be able to optimize therapeutically effective local dosages without undue experimentation
The amount of β-hairpin peptidomimetics administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgement of the prescribing physician
The antimicrobial therapy may be repeated intermittently while infections are detectable or even when they are not detectable The therapy may be provided alone or in combination with other drugs, such as for example antibiotics or other antimicrobial agents
Normally, a therapeutically effective dose of the β-hairpin peptidomimetics described herein will provide therapeutic benefit without causing substantial toxicity
Hemolysis of red blood cells is often employed for assessment of toxicity of related compounds such as protegrin or tachyplesin Values are given as %-lysιs of red blood cells observed at a concentration of 1 OOμg/ml Typical values determined for catiomc peptides such as protegrin and tachyplesin range between 30-40% with average MIC-values of 1-5 μg/ml over a wide range of pathogens Normally, β- hairpm peptidomimetics of the invention will show hemolysis in a range of 0 5-10%, often in a range of 1-5%, at activity levels comparable to those mentioned above for protegrin and tachyplesin Thus preferred compounds exhibit low MIC-values and low %-hemolysιs of red blood cells observed at a concentration of 1 OOμg/ml
Toxicity of the β-hairpin peptidomimetics of the invention herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e g , by determining the LD50 (the dose lethal to 50% of the population) or the LD,oo(the dose lethal to 100% of the population) The dose ratio between toxic and therapeutic effect is the therapeutic index Compounds which exhibit high therapeutic indices are preferred The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in humans The dosage of the β -hairpin peptidomimetics of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity The dosage may vary within the range depending upon the dosage form employed and the route of administration utilized The exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (see, e g Fingl et al 1975, In The Pharmacological Basis of Therapeutics,
Ch i, p i)
The following Examples illustrate the invention in more detail but are not intended to limit its scope in any way The following abbreviations are used in these Examples
HBTU 1 -benzotπazol- 1 -yl-tetramethylurounium hexafluorophosphate (Knon et al
Tetrahedron Lett 1989, 30, 1927-1930), HOBt 1 -hydroxybenzotπazole,
DIEA diisopropylethylamine,
HOAT 7-aza- 1 -hydroxybenzotnazole,
HATU 0-(7-aza-benzotπazole-l-yl)-N,N,N',N'-tetramethyluronoιum hexafluorophosphate (Carpino et al Tetrahedron Lett 1994, 55, 2279-2281)
Examples
1. Peptide synthesis
Coupling of the first protected amino acid residue to the resin
0 5 g of 2-chlorotπtylchlonde resin (Barlos et al Tetrahedron Lett 1989, 30, 3943-3946) (0 83 mMol/g, 0415 mmol) was filled into a dned flask The resin was suspended in CH2C12 (2 5 ml) and allowed to swell at room temperature under constant stirnng for 30 min The resm was treated with 0415 mMol (leq) of the first suitably protected amino acid residue (see below) and 284 μl (4eq) of diisopropylethylamme (DIEA) in CH2C12 (2 5 ml), the mixture was shaken at 25°C for 4 hours The resm colour changed to purple and the solution remained yellowish The resin was shaken (CH2C12 /MeOH/DIEA 17/2/1), 30 ml for 30 mm, then washed in the following order with CH2C12 (lx), DMF (lx), CH2Cl2 (lx), MeOH (lx), CH2Cl2(lx), MeOH (lx), CH2C12 (2x), Et20 (2x) and dried under vacuum for 6 hours
Loading was typically 0 6-0 7 mMol/g The following preloaded resm was prepared Fmoc-ProO-chlorotπtylresm
Synthesis of the fully protected peptide fragment
The synthesis was earned out using a Syro-peptide synthesizer (Multisyntech) using 24 to 96 reaction vessels In each vessel was placed 60 mg (weight of the resm before loading) of the above resm The following reaction cycles were programmed and carried out
Step Reageni t Time
1 CH2C12, wash and swell (manual) 3 x 1 min
2 DMF, wash and swell 1 x 5 mm
3 40 % pipeπdine/DMF 1 x 5 min
4 DMF, wash 5 x 2 min
5 5 equiv Fmoc amino acid/DMF
+ 5 eq HBTU + 5 eq HOBt
6 DMF, wash 4 x 2 min
7 CH2C12, wash (at the end of the synthesis) 3 x 2 min
Steps 3 to 6 are repeated to add each amino-acid
Cleavage of the fully protected peptide fragment
After completion of the synthesis, the resin was suspended in 1 ml (0 39 mMol) of 1 % TFA in CH2C12 (v/v) for 3 minutes, filtered and the filtrate was neutralized with 1ml ( 1 17 mMol, 3eq ) of 20% DIEA in CH2C12 (v/v) This procedure was repeated twice to ensure completion of the cleavage The filtrate was evaporated to dryness and the product was fully deprotected [cleavage mixture containing 95% tnfluoroacetic acid (TFA), 2 5% water and 2 5% trusopropylsilane (TIS)] to be analyzed by reverse phase-HPLC (column C|8) and ESI-MS to monitor the efficiency of the linear peptide synthesis
Cyclization of the linear peptide
100 mg of the fully protected linear peptide were dissolved in DMF (9 ml, cone 10 mg/ml) Then 41 8 mg (0 1 10 mMol, 3 eq ) of HATU, 14 9 mg (0 1 10 mMol, 3 eq) of HOAt and 1 ml (0 584 mMol) of 10% DIEA in DMF (v/v) were added and the mixture vortexed at 20°C for 16 hours and subsequently concentrated under high vacuum. The residue was partitioned between CH2C12 and H20/CH3CN (90/10 v/v). The CH2C12 phase was evaporated to yield the fully protected cyclic peptide
Deprotection and purification of the cyclic peptide-
The cyclic peptide obtained was dissolved in 1 ml of the cleavage mixture containing 95% tnfluoroacetic acid (TFA), 2.5% water and 2.5% tnisopropylsilane (TIS). The mixture was left to stand at 20°C for 2.5 hours and then concentrated under vacuum. The residue was dissolved in a solution of H20/acetιc acid (75/25 v/v) and the mixture extracted with di-isopropylether.
The water phase was dried under vacuum and then the product purified by preparative reverse phase HPLC.
After lyophihsation products were obtained as a white powder and analysed by ESI-MS. The analytical data comprising HPLC retention times and ESI-MS are shown in table 1. Analytical HPLC retention times (RT, in minutes) were determined using a VYDAC 218MS5215 column with the following solvents A (H20 + 0 02% TFA) and B (CH3CN) and the gradient. 0 min- 92%A, 8%B; 8 min: 62%A 38%B; 9-12 mm. 0% A, 100%B.
Examples 1-7 (n=12) are shown in table 1. The peptides were synthesized starting with the amino acid Pro which was grafted to the resm Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resιn-Pro- DPro-P12-Pl 1-P10-P9-P8-P7-P6- P5-P4-P3-P2-P1, cleaved from the resm, cychzed, deprotected and purified as indicated. HPLC-retention times (minutes) were determined using the gradient described above-
Ex.l (5.73; 6.29)*; Ex.2 (5.13; 5.51, 5.75)*; Ex.3 (4.83; 5.37)*; Ex.4 (4 79; 5 43)*; Ex.5 (5.27;
5.85)* Ex.6 (5.31 ; 6.03); Ex.7 (4.59).
* double peaks which show both correct MS and chiral amino acid analysis. At 60° only one peak is observed.
Table /: Examples (Ex)
Ex. SEQ ID PI P2 P3 P4 P5 P6 P7 P8 P9 PIO Pl l P12 Template Purity%a) [m/z], z=2
1 SEQ ID NO: 1 Arg Trp Leu Lys Lys Arg Arg Trp Leu Tyr Tyr Arg DProLPro 100 1000.3
2 SEQ ID NO:2 Arg Tip Leu Lys Lys Arg Arg Trp Lys Tyr Val Arg DProLPro 100 976.1
3 SEQ ID NO 3 Arg Tip Leu Lys Lys Arg Arg Trp Lys Thr Tyr Arg DProLPro 54 977.0
4 SEQ ID NO 4 Arg Trp Leu Lys Lys Arg Arg Trp Lys Gin Tyr Arg DProLPro 100 991.1
5 SEQ ID NO:5 Arg Trp Leu Val Lys Arg Arg Tφ Lys Tyr Tyr Arg DPro Pro 100 993.4
6 SEQ ID NO:6 Arg Trp Leu Lys Lys Arg Arg Tφ Val Tyr Tyr Arg °ProLPro 100 993.5
7 SEQ ID NO:7 Arg Tip Leu Lys Lys Arg Arg Tφ Lys Tyr Gin Arg DProLPro 100 991.2
8 SEQ ID NO:8 Arg Trp Leu Lys Lys Arg Arg Tφ Lys Tyr Leu Arg DProLPro 24 983.1
a) %-puritity of compounds after prep. HPLC.
2. Biological methods
2.1. Preparation of the peptides.
Lyophilized peptides were weighed on a Microbalance (Mettler MT5) and dissolved in sterile water containing 0 01% acetic acid
2.2. Antimicrobial activity of the peptides.
The selective antimicrobial activities of the peptides were determined by the standard NCCLS broth microdilution method (see ref 1 , below) examined m sterile 96-wells plates (Nunclon polystyrene microtiter plates) in a total volume of 100 μl Innocula of the microorganisms were prepared with 0 5 Mcfarland standard and then diluted into Mueller-Hinton (MH) broth to give appr 10 colony forming units (CFU)/ml for bacteria Aliquots (50 μl) of the innocula were added to 50 μl of MH broth containing the peptide in serial twofold dilutions For the screening of the peptides displaying selectivity, the following microorganisms were used Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (P aeruginosa ) (ATCC 27853), Staphylococcus aureus (ATCC 29213 and ATCC 25923), and clinical isolates of Pseudomonas aeruginosa (P aeruginosa) V02 16085 and Acinetobacter (Acinetobacter V04 19905/1, Acinetobacter V 2 21143/1 and Acinetobacter V12 21193/1) Antimicrobial activities of the peptides were expressed as the minimal inhibitory concentration (MIC) in μg/ml at which no visible growth was observed after 18-20 hours of incubation of the microtiter plates at 37°C
2.3. Antimicrobial activity of the peptides in 0.9% saline
Salt sensitivity of the peptides was tested by the microtiter serial dilution assay as described above Only MH broth was replaced by MH broth containing 0 9 % NaCl
2.4. Antimicrobial activity of the peptides in Human serum
Serum binding of the peptides was tested by the microtiter serial dilution assay as described above Only MH broth was replaced by MH broth containing 90% human serum (BioWhittaker)
2.5. Hemolysis
The peptides were tested for their hemolytic activity against human red blood cells (hRBC) Fresh hRBC were washed three times with phosphate buffered saline (PBS) by centrifugation for 10 min at 2000 x g Peptides at a concentration of 100 μg/ml were incubated with 20% v/v hRBC for 1 hour at 37°C The final erythrocyte concentration was appr. 0.9 x 109/ml. A value of 0% resp 100% cell lysis was determined by incubation of the hRBC in the presence of PBS alone and resp. 0.1% Tnton X-100 in H2O The samples were centrifuged and the supernatant was 20 fold diluted in PBS buffer and the optical density (OD) of the sample at 540 nM was measured The 100% lysis value (OD540H2O) gave an OD of approximately 1.6-2.0 Percent hemolysis was calculated as follows- (OD54θpeptιde/OD54θH2θ) xl00%
2.6. Results
The results of the experiments described above are indicated in Table 2 and Table 3, herein below
References
1. National Committee for Clinical Laboratory Standards 1993 Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 3rd ed. Approved standard M7-A3 National Committee for Clinical laboratory standards, Villanova, Pa
2 Mossman T J Immunol Meth 1983, 65, 55-63
3 Berndge MV, Tan AS. Archives of Biochemistry & Biophysics 1993, 303, 474-482
Table 2. Minimal inhibitory concentrations (MIC in μg/ml) in Mueller-Hinton broth and percentage hemolyses at a concentration of 100 μg/ml of peptid
n.d.: not determined
Table 3: Minimal inhibitory concentrations (MIC in μg/ml) in Mueller-Hinton broth containing 0.9% NaCl

Claims

1. Compounds of the general formula
wherein
is a group of one of the formulae
01) (a2)
(h) (M)
(i2)
(i3) (i4) ϋ)
(n) (o) (P)
wherein
is the residue of an L-α-amino acid with B being a residue of formula -NR20CH(R7 ' )- or the enantiomer of one of the groups Al to A69 as defined hereinafter;
y
is a group of one of the formulae
A1 A2 A3 A4
A5 A6 A7 A8 A9
A10 A11 A12 A13 A14
A20 A21 A22 A23 A24
A26 A27 A28
A30 A31 A32 A33
A38 A39 A40 A41 A42
A58 A59 A60 A61 A62
A63 A64 A65 A66
A85 A86
A100 A101 A102 A103 A104
R' is H; lower alkyl; or aryl-lower alkyl;
R2 is H; alkyl; alkenyl; -(CH2)m(CHR6l)sOR55; -(CH2)m(CHR6')sSR56;
-(CH2)m(CHR6l)sNR33R34; -(CH2)m(CHR6')sOCONR33R75;
-(CH2)m(CHR6l)sNR20CONR33R82; -(CH2)o(CHR61)sCOOR57;
-(CH2)o(CHR6l)sCONR58R59; -(CH2)o(CHR6l)sPO(OR60)2;
-(CH2)0(CHR6I)S S02R62; or -(CH2)„(CHR61)SC6H4R8; R3 is H; alkyl; alkenyl; -(CH2)m(CHR6l)sOR55; -(CH2)m(CHR6l)sSR56;
-(CH2)m(CHR61)sNR33R34; -(CH2)rn(CHR61)sOCONR33R75;
-(CH2)m(CHR61)sNR20CONR33R82; -(CH2)0(CHR61)sCOOR57;
-(CH2)0(CHR6,)sCONR58R59 ; -(CH2)o(CHR6,)sPO(OR60)2;
-(CH2)0(CHR6')S S02R62; or -(CH2)0(CHR6,)SC6H4R8; R4 is H; alkyl; alkenyl; -(CH2)m(CHR6l)sOR55; -(CH2)nι(CHR6')sSR56; -(CH2)nι(CHR6')sNR33R34;
-(CH2)m(CHR61)sOCONR33R75; -(CH2)m(CHR6l)sNR20CONR33R82;
-(CH2)p(CHR6l)sCOOR 7; -(CH2)p(CHR61)sCONR58R59; -(CH2)p(CHR6')sPO(OR60)2;
-(CH2)P(CHR6')S S02R62; or -(CH2)0(CHR6')SC6H4R8; R5 is alkyl; alkenyl; -(CH2)0(CHR6l)sOR55; -(CH2)0(CHR6I)SSR56; -(CH2)0(CHR61)SNR33R34;
-(CH2)o(CHR61)sOCONR33R75; -(CH2)o(CHR61)sNR20CONR33R82;
-(CH2)o(CHR6,)sCOOR57; -(CH2)o(CHR6l)sCONR58R59; -(CH2)o(CHR6')sPO(OR60)2; -(CH2)0(CHR61)S S02R62; or -(CH2)0(CHR6,)SC6H4R8; R6 is H; alkyl; alkenyl; -(CH2)0(CHR6')sOR55; -(CH2)0(CHR61)SSR56; -(CH2)0(CHR61)SNR33R34;
-(CH2)0(CHR6 l)sOCONR33R75 ; -(CH2)0(CHR6 ')SNR20CONR33R82 ;
-(CH2)o(CHR61)sCOOR57; -(CH2)o(CHR6,)sCONR58R59; -(CH2)„(CHR61)sPO(OR60)2; -(CH2)0(CHR61)S S02R62; or -(CH2)0(CHR6,)SC6H4R8;
R7 is alkyl; alkenyl; -(CH2)q(CHR61)sORss; -(CH2)q(CHR61)sNR33R34;
-(CH2)q(CHR61)sOCONR33R75; -(CH2)q(CHR61)-NR20CONR33R82;
-(CH2)r(CHR61)sCOOR57; -(CH2)r(CHR61)sCONR58R59; -(CH2)r(CHR6l)sPO(OR60)2;
-(CH2)r(CHR61)sS02R62; or -(CH2)r(CHR6l)s C6H4R8; R is H; Cl; F; CF3; N02; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;
-(CH2)o(CHR6l)s0R55; -(CH2)0(CHR61)SSR56; -(CH2)0(CHR61)NR33R34 ;
-(CH2)o(CHR6l)sOCONR33R75; -(CH2)o(CHR6')sNR20CONR33R82;
-(CH2)o(CHR6l)sCOOR57; -(CH2)o(CHR6l)sCONR58R59; -(CH2)o(CHR6 l)sPO(OR60)2;
-(CH2)0(CHR61)sS02R62; or -(CH2)0(CHR6l)sCOR64; R9 is alkyl; alkenyl; -(CH2)0(CHR61)sOR55; -(CH2)0(CHR61)SSR56; -(CH2)o(CHR6')sNR3 R34;
-(CH2)o(CHR6l)-OCONR33R75; -(CH2)o(CHR61)-NR20CONR33R82;
-(CH2)o(CHR6 ' )sCOOR"; -(CH2)0(CHR61 )sCONR58R59; -(CH2)0(CHR6 ' )SPO(OR60)2;
-(CH2)0(CHR61)S S02R62; or -(CH2)0(CHR6I)SC6H4R8; R10 is alkyl; alkenyl; -(CH2)0(CHR61)s0R55; -(CH2)0(CHR61)SSR56; -(CH2)0(CHR6I)SNR33R34; -(CH2)0(CHR61)sOCONR33R75; -(CH2)o(CHR61)sNR20CONR33R82;
-(CH2)o(CHR6')sCOOR57; -(CH2)o(CHR6l)sCONR58R59; -(CH2)o(CHRδl)sPO(OR60)2;
-(CH2)0(CHR6')S S02R62; or -(CH2)0(CHR6,)SC6H4R8; R" is H; alkyl; alkenyl; -(CH2)„,(CHR6')sOR55; -(CH2)m(CHR6l)sNR33R34;
-(CH2)m(CHR6 ' )sOCONR33R75; -(CH2)m(CHR6 ' )SNR 0CONR33R82; -(CH2)o(CHR6 l)sCOOR57; -(CH2)0(CHR6')sCONR58R59; -(CH2)0(CHR6I)SPO(OR60)2;
-(CH2)0(CHR6I)SS02R62; or -(CH2)0(CHR6,)S C6H4R8; R12 is H; alkyl; alkenyl; -(CH2)m(CHR6')s0R55; -(CH2)m(CHR61)sSR56;
-(CH2)m(CHR61)sNR33R3 ; -(CH2)m(CHR61)sOCONR33R75;
-(CH2)m(CHR61)sNR20CONR33R82; -(CH2)r(CHR61)sCOORS7; -(CH2)r(CHR61)sCONR58R59; -(CH2)r(CHR6l)sPO(OR60)2; -(CH2)r(CHR6l)s S02R62; or -(CH2)r(CHR6')sC6H4R8;
R'3 is alkyl; alkenyl; -(CH2)q(CHR6,)sOR55; -(CH2)q(CHR61)sSR56; -(CH2)q(CHR6l)sNR33R34;
-(CH2)q(CHR6 ')sOCONR33R75 ; -(CH2)q(CHR6 ' )SNR20CONR33R82 ;
-(CH2)q(CHR6l)sCOOR57; -(CH2)q(CHR61)sCONR58R59; -(CH2)q(CHR61)sPO(OR60)2;
-(CH2)q(CHR6,)s S02R62; or -(CH2)q(CHR6l)sC6H4R8; R14 is H; alkyl; alkenyl; -(CH2)m(CHR6l)sOR55; -(CH2)nι(CHR6l)sNR33R34; -(CH2)m(CHR6')sOCONR33R75; -(CH2)m(CHR61)sNR20CONR33R82; -(CH2)q(CHR61)sCOOR57, -(CH2)q(CHR6,)sCONR58R59, -(CH2)q(CHR61)-PO(OR60)2, -(CH2)q(CHR61)sSOR62, or -(CH2)q(CHR6')s H4R8, R15 is alkyl, alkenyl, -(CH2)0(CHR6l)sOR55, -(CH2)0(CHR61)SSR56, -(CH2)0(CHR61)SNR33R34, -(CH2)0(CHR61)sOCONR33R75, -(CH2)0(CHR6')SNR20CONR33R82, -(CH2)0(CHR61)sCOOR57, -(CH2)0(CHR6')sCONR58R59, -(CH2)o(CHR6l)-PO(OR60)2,
-(CH2)o(CHR6')s S02R62, or -(CH2)0(CHR6,)AH4R8, R16 is alkyl, alkenyl, -(CH2)0(CHR6l)5OR55, -(CH2)o(CHR61)sSR56, -(CH2)0(CHR61)SNR33R34, -(CH2)o(CHR61)sOCONR33R75, -(CH2)0(CHR6l)sNR20CONR33R82, -(CH2)0(CHR61)sCOOR57, -(CH2)o(CHR61)sCONR58R59, -(CH2)o(CHR6')sPO(OR60)2, -(CH2)0(CHR61)S S02R62, or -(CH2)0(CHR6I)SC6H4R8,
R17 is alkyl, alkenyl, -(CH2)q(CHR6,)sOR55, -(CH2)q(CHR61)sSR56, -(CH2)q(CHR6,)sNR33R34, -(CH2)q(CHR6l)sOCONR33R75, -(CH2)q(CHR61)sNR20CONR33R82, -(CH2)q(CHR6')sCOOR57, -(CH2)q(CHR61)sCONR58R59, -(CH2)q(CHR6')sPO(OR60)2, -(CH2)q(CHR6')s S02R62, or -(CH2)q(CHR6l)sC6H4R8, R'8 is alkyl, alkenyl, -(CH2)p(CHR61).OR55, -(CH2)P(CHR6')SSR56, -(CH2)P(CHR61)SNR33R34, -(CH2)P(CHR6 ' )sOCONR33R75, -(CH2)P(CHR6 ' )SNR20CONR33R82 , -(CH2)p(CHR6l)sCOOR57, -(CH2)p(CHR61)sCONR58R59, -(CH2)P(CHR6I)SPO(OR60)2, -(CH2)P(CHR6')S S02R62, or -(CH2)o(CHR61)sC6H4R8, R19 is lower alkyl, -(CH2)p(CHR61)sOR55, -(CH2)P(CHR6I)SSR56, -(CH2)P(CHR6I)SNR33R34, -(CH2)p(CHR61)sOCONR33R75, -(CH2)P(CHR61)SNR20CONR33R82,
-(CH2)p(CHR6,)sCOOR57, -(CH2)p(CHR6l)sCONR58R59, -(CH2)p(CHR6l)sPO(OR60)2, -(CH2)p(CHR61)s S02R62, or -(CH2)0(CHR61)SC6H4R8, or R18 and R19 taken together can form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or R20 is H, alkyl, alkenyl, or aryl-lower alkyl,
R21 is H, alkyl, alkenyl, -(CH2)0(CHR61)sOR55, -(CH2)0(CHR6 I)SSR56, -(CH2)0(CHR6I)SNR33R34, -(CH2)o(CHR6')sOCONR33R75, -(CH2)o(CHR6')sNR20CONR33R82, -(CH2)o(CHR6l)sCOOR57, -(CH2)o(CHR6,)-CONR58R59, -(CH2)o(CHR6')sPO(OR60)2, -(CH2)0(CHR61)S S02R62, or -(CH2)0(CHR61)SC6H4R8, R22 is H, alkyl, alkenyl, -(CH2)0(CHR6l)sOR55, -(CH2)0(CHR61)SSR56, -(CH2)0(CHR6I)SNR33R34, -(CH2)o(CHR6')sOCONR33R7S, -(CH2)o(CHR61)sNR20CONR33R82, -(CH2)o(CHR6')sCOOR57, -(CH2)o(CHR6l)sCONR58R59, -(CH2)o(CHR6l)sPO(OR60)2, -(CH2)0(CHR6I)S S02R62, or -(CHJUCHR^ R-R8, R23 is alkyl, alkenyl, -(CH2)0(CHR6')sOR55, -(CH2)0(CHR6')SSR56, -(CH2)0(CHR6I)SNR33R34, -(CH2)0(CHR6')sOCONR33R75, -(CH2)o(CHR61)sNR20CONR33R82,
-(CH2)o(CHR6')sCOOR57, -(CH2)o(CHR6,)sCONR58R59, -(CH2)o(CHR61)sPO(OR60)2, -(CH2)0(CHR6,)S S02R62; or -(CH2)0(CHR61)AH-ιR8; R24 is alkyl; alkenyl; -(CH2)0(CHR6')sOR55; -(CH2)0(CHRδl)-SR5δ; -(CH2)0(CHR6')SNR33R34; -(CH2)o(CHR6')sOCONR33R75; -(CH2)o(CHR6,)sNR20CONR33R82; -(CH2)o(CHR61)sCOORS7; -(CH2)o(CHR61)sCONR58R59; -(CH2)o(CHR61)sPO(OR60)2; -(CH2)0(CHR6')S S02R62; or -(CH2)0(CHR51)SC6H4R8;
R25 is H; alkyl; alkenyl; -(CH2)m(CHR6')sOR55; -(CH2)m(CHR6')sSR56; -(CH2)m(CHR61)sNR33R34; -(CH2)m(CHR61)sOCONR33R75; -(CH2)m(CHR61)sNR20CONR33R82; -(CH2)o(CHR61)sCOOR57; -(CH2)0(CHR6')sCONR58R59; -(CH2)o(CHR61)sPO(OR60)2; -(CH2)o(CHR61)sS02R62; or -(CH2)0(CHR61)AH4R8;
R26 is H; alkyl; alkenyl; -(CH2)m(CHR61)sOR55; -(CH2)m(CHRδl)sSR5δ; -(CH2)m(CHR6l)sNR33R34; -(CH2)m(CHR61)sOCONR33R75;
-(CH2)m(CHR61)sNR20CONR33R82; -(CH2)o(CHR6l)sCOOR57; -(CH2)o(CHR6').CONR58R59; -(CH2)o(CHR61)sPO(OR60)2; -(CH2)0(CHR6,)S S02R62; or -(CH2)0(CHR6I)SC6H4R8; or R25 and R26 taken together can form: -(CH2)2.6-; -(CH2)rO(CH2)r-; -(CH2)rS(CH2)r-; or -(CH2)rNR57(CH2)r-; R27 is H; alkyl; alkenyl; -(CH2)0(CHR6')sOR5S; -(CH2)0(CHR61)SSR56; -(CH2)0(CHR6')SNR33R34; -(CH2)0(CHR6 ' )sCOOR57; -(CH2)0(CHR61 )sCONR58R59; -(CH2)0(CHRδl )sOCONR33R75 ; -(CH2)0(CHR6 ' )SNR20CONR33R82; -(CH2)0(CHR6 ' )SPO(OR60)2; -(CH2)0(CHR61)S S02R62; or -(CH2)0(CHR61)SC6H4R8;
R28 is alkyl; alkenyl; -(CH2)0(CHR6l)s-OR55; -(CH2)0(CHR61)S SR56; -(CH2)0(CHR61)S NR33R34; -(CH2)o(CHR6,)sOCONR33R75; -(CH2)o(CHR61)sNR20CONR33R82; -(CH2)0(CHR6I)S COOR57; -(CH2)0(CHR6')S CONR58R59; -(CH2)0(CHR6I)S PO(OR60)2; -(CH2)0(CHR61)S S02R62; or -(CH2)0(CHR6I)S C6H-.R8; R29 is alkyl; alkenyl; -(CH2)0(CHR61)sOR55; -(CH2)o(CHR6l)-SR56; -(CH2)0(CHR6,)SNR33R34; -(CH2)o(CHR61)sOCONR33R75; -(CH2)o(CHR61)sNR20CONR33R82; -(CH2)o(CHR6l)sCOOR57; -(CH2)o(CHR6')sCONR58R59; -(CH2)o(CHR61)sPO(ORδ0)2; -(CH2)0(CHRδl)s S02R62; or -(CH2)0(CHRδl)sC6H4R8; R30 is H; alkyl; alkenyl; or aryl-lower alkyl; R31 is H; alkyl; alkenyl; -(CH2)p(CHR6l)-OR55; -(CH2)p(CHRδl)sNR33R34; -(CH2)P(CHR6 ' )sOCONR33R75 ; -(CH2)P(CHR6 ' )SNR20CONR33R82 ; -(CH2)o(CHR61)sCOOR57; -(CH2)o(CHR61)sCONR58R59; -(CH2)o(CHRδl)sPO(OR60)2; -(CH2)0(CHR61)sS02R62; or -(CH2)0(CHR61)- FLR8; R32 is H; lower alkyl; or aryl-lower alkyl; R33 is H; alkyl, alkenyl; -(CH2)m(CHRδl)sOR5S; -(CH2)m(CHRδl)sNR34R63; -(CH2)m(CHR6,)sOCONR75R 2; -(CH2)m(CHR61)sNR20CONR78R82; -(CH2)o(CHR6l)sCOR64, -(CH2)o(CHRδl)s-CONR58R59, -(CH2)o(CHRδl)sPO(OR60)2, -(CH2)„(CHRδl)s S02R62, or -(CH2)0(CHR61)AH4R8, R34 is H, lower alkyl, aryl, or aryl-lower alkyl,
R33 and R34 taken together can form -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-,
R35 is H, alkyl, alkenyl, -(CH2)m(CHRδl)sOR55, -(CH2)m(CHR6 l)sNR33R34, -(CH2)m(CHR61)sOCONR33R75, -(CH2)m(CHR61)sNR20CONR33R82, -(CH2)p(CHRδl)sCOOR57, -(CH2)p(CHR6l)sCONR58R59, -(CH2)P(CHR6')SPO(OR60)2, -(CH2)p(CHR6,)sS02R62, or -(CH2)P(CHR61)S C6H4R8, R36 is H, alkyl, alkenyl, -(CH2)0(CHR61)sOR55, -(CH2)p(CHRδl)sNR33R34, -(CH2)p(CHR61)sOCONR33R75, -(CH2)P(CHR6 I)SNR20CONR33R82, -(CH2)p(CHR6l)sCOOR57, -(CH2)p(CHR6')5CONR58R59, -(CH2)p(CHR61)sPO(OR60)2, -(CH2)p(CHR6l)sS02R62, or -(CH2)0(CHR6')S C6H-,R8, R37 is H, F, Br, Cl, N02, CF3, lower alkyl, -(CH2)p(CHRδ')sOR55, -(CH2)p(CHRδl)sNR33R34, -(CH2)p(CHR6')sOCONR33R75, -(CH2)p(CHR6 l)sNR20CONR33R82,
-(CH2)0(CHR61)sCOOR57, -(CH2)0(CHR6l)sCONR58R59, -(CH2)o(CHR6l)-PO(OR60)2, -(CH2)0(CHR6')sS02R62, or -(CH2)0(CHR6')S C^R8, R38 is H, F, Br, Cl, N02, CF3, alkyl, alkenyl, -(CH2)p(CHR6 l)sOR55, -(CH2)p(CHR61)sNR33R34, -(CH2)p(CHR6,)sOCONR33R75, -(CH2)p(CHR6l)sNR20CONR33R82, -(CH2)o(CHR6l)sCOOR57, -(CH2)0(CHR6')sCONR58R59, -(CH2)o(CHR61)sPO(OR60)2,
-(CH2)0(CHR61)sS02R62, or -(CH2)0(CHRδ l)sC6H4R8, R39 is H, alkyl, alkenyl, or aryl-lower alkyl, R40 is H, alkyl, alkenyl, or aryl-lower alkyl,
R41 is H, F, Br, Cl, N02, CF3) alkyl, alkenyl, -(CH2)p(CHR6 l)sOR5S, -(CH2)P(CHR61)SNR33R34, -(CH2)p(CHRδl)sOCONR33R75, -(CH2)P(CHR6')SNR20CONR33R82,
-(CH2)0(CHR6')sCOOR57, -(CH2)0(CHRδl)sCONR5 R59, -(CH2)o(CHR61)sPO(OR60)2, -(CH2)o(CHR6,)sS02R62, or -(CH2)0(CHR6,)S CftR8, R42 is H, F, Br, Cl, N02, CF3, alkyl, alkenyl, -(CH2)p(CHRδ l)sOR55, -(CH2)P(CHR61)SNR33R34, -(CH2)P(CHR6 ' )SOCONR33R75 , -(CH2)p(CHRδ ')-NR20CONR33R82, -(CH2)o(CHR6')sCOOR57, -(CH2)0(CHR6')sCONR58R59, -(CH2)o(CHR6 l)sPO(OR60)2,
-(CH2)0(CHRδ')sS02R62, or -(CH2)0(CHR61)S I^R8, R43 is H, alkyl, alkenyl, -(CH2)„,(CHR6')sOR55, -(CH2)m(CHRδ')sNR33R34, -(CH2)m(CHR61)sOCONR33R75, -(CH2)m(CHR61)sNR20CONR33R82, -(CH2)0(CHR6 ' )sCOOR57, -(CH2)0(CHRδ ' )sCONR58R59, -(CH2)0(CHR6 ' )sPO(ORδ0)2, -(CH2)0(CHRδl)sS02R62, or -(CH2)0(CHRδl)s
R44 is alkyl, alkenyl, -(CH2)r(CHRδl)sOR55, -(CH2)r(CHR6 l)sSR56, -(CH2)r(CHRδ')sNR33R34, -(CH2)r(CHR6,)5OCONR33R75; -(CH2)r(CHR6l)sNR20CONR33R82; -(CH2)r(CHRδ')sCOOR57; -(CH2)r(CHR6l)sCONR58R59; -(CH2)r(CHR61)-PO(OR60)2; -(CH2)r(CHR61)- S02R62; or -(CH2).(CHR61)SC6H4R8; R45 is H; alkyl; alkenyl; -(CH2)0(CHR61)sOR55; -(CH2)0(CHRδl)sSR56; -(CH2)0(CHR61)SNR33R34; -(CH2)0(CHR6')SOCONR 3R75; -(CH2)o(CHR61)sNR20CONR33R82;
-(CH2)o(CHR6l)sCOOR57; -(CH2)s(CHR6l)sCONR58R59; -(CH2)-(CHR6,)sPO(ORδ0)2; -(CH2)S(CHR6,)S S02R62; or -(CH2)S(CHR6,)SC6H4R8; R46 is H; alkyl; alkenyl; or -(CH2)0(CHRδl)pC6H4R8; R47 is H; alkyl; alkenyl; or -(CH2)0(CHR61)sOR55; R48 is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;
R49 is H; alkyl; alkenyl; -(CHR61)sCOOR57; (CHR61)-CONR58R59; (CHR6I)SPO(OR60)2;
-(CHR6l)sSOR62; or -(CHR61)SC6H4R8; R50 is H; lower alkyl; or aryl-lower alkyl;
R5' is H; alkyl; alkenyl; -(CH2)m(CHRδ')sOR55; -(CH2)m(CHR6')sSR56; -(CH2)m(CHR6')sNR33R34; -(CH2)m(CHR61)sOCONR33R75;
-(CH2)m(CHR6l)sNR20CONR33R82; -(CH2)o(CHR6l)sCOOR57; -(CH2)o(CHRδ,)sCONR58R59; -(CH2)0(CHR ')pPO(ORδo)2; -(CH2)p(CHR61)s S02R62; or -(CH2)p(CHRδl)AH4R8; R52 is H; alkyl; alkenyl; -(CH2)m(CHR6')sOR55; -(CH2)m(CHR6l)5SR56; -(CH2)m(CHR6l)sNR33R34; -(CH2)m(CHRδl)sOCONR33R75;
-(CH2)m(CHR6l)sNR20CONR33R82; -(CH2)o(CHRδ')sCOOR57; -(CH2)o(CHR61)-CONR58R59; -(CH2)o(CHR6')pPO(OR60)2; -(CH2)p(CHRδl)s S02R62; or -(CH2)p(CHR61)sC6H4R8; R" is H; alkyl; alkenyl; -(CH2)m(CHR6l)sOR55; -(CH2)m(CHRδl)sSR56; -(CH2)m(CHR61)sNR33R34; -(CH2)m(CHR6')sOCONR33R75;
-(CH2)ni(CHR61)sNR20CONR33R82; -(CH2)o(CHR6')sCOOR57; -(CH2)o(CHRδl)sCONR58R59; -(CH2)0(CHR6l)pPO(OR60)2; -(CH2)P(CHR6')S S02R62; or -(CH2)P(CHR6I)AH4R8; R54 is H; alkyl; alkenyl; -(CH2)m(CHR6,)sOR55; -(CH2)m(CHRδ')5NR33R34; -(CH2)m(CHR61)sOCONR33R75; -(CH2)m(CHRδl)sNR20CONR33R82;
-(CH2)0(CHR6,)COOR57; -(CH2)0(CHRδ,)sCONR58R59; or -(CH2)0(CHR61)S C6H-,R8; R55 is H; lower alkyl; lower alkenyl; aryl-lower alkyl; -(CH2),„(CHR6l)sOR57; -(CH2)m(CHR61)sNR34R63; -(CH2)m(CHR61 )sOCONR75R82;
-(CH2)m(CHR6l)sNR20CONR78R82; -(CH2)0(CHR61)--COR64; -(CH2)0(CHRδl)COOR57; or -(CH2)0(CHR6l)sCONR58R59;
R5δ is H; lower alkyl; lower alkenyl; aryl-lower alkyl; -(CH2)m(CHR6,)sOR57; -(CH2)m(CHR6l)sNR34R63; -(CH2)m(CHR61)-OCONR75R82; -(CH2)m(CHR61)sNR20CONR78R82; -(CH2)0(CHR6,)s-COR64; or -(CH2)0(CHR6l)sCONR58R59; R is H; lower alkyl; lower alkenyl; aryl lower alkyl; or heteroaryl lower alkyl; R58 is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-lower alkyl; R is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-lower alkyl; or R58 and R59 taken together can form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; R60 is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl; Rδl is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; -(CH2)mOR55; -(CH2)mNR33R34; -(CH2)mOCONR75R82; -(CH2)mNR20CONR78R82; -(CH2)0COOR37; -(CH2)0NR58R59; or -(CH2)oPO(COR60)2; R62 is lower alkyl; lower alkenyl; aryl, heteroaryl; or aryl-lower alkyl;
R63 is H; lower alkyl; lower alkenyl; aryl, heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; -COR64; -COOR57; -CONR58R59; -S02R62; or -PO(OR60)2;
R34and R63 taken together can form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; R64 is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; -(CH2)p(CHRδl)sOR65; -(CH2)P(CHR61)SSR66; or -(CH2)P(CHR61)SNR34R63; -(CH2)p(CHR6,)sOCONR75R82; -(CH2)P(CHR61)SNR20CONR78R82;
R65 is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl; heteroaryl-lower alkyl; -COR57;
-COOR57; or -CONR58R59; Rδδ is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl; heteroaryl-lower alkyl; or -CONR58R59; m is 2-4; o is 0-4; p is 1 -4; q is 0-2; r is 1 or 2; s is 0 or 1 ;
Z is a chain of 12 α-amino acid residues, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, whereby these amino acid residues are, depending on their position in the chain, Gly or Pro, or of formula -A-CO-, or of formula -B-CO-, or of one of the types
C: -NR20CH(R72)CO-;
D: -NR20CH(R73)CO-;
E: -NR20CH(R74)CO-;
F: -NR20CH(R84)CO-; and
H: -NR20-CH(CO-)-(CH2) ..7-CH(CO-)-NR20-;
-NR20-CH(CO-)-(CH2)pSS(CH2)p-CH(CO-)-NR20-; -NR20-CH(CO-)-(-(CH2)pNR20CO(CH2)p-CH(CO-)-NR20-; and -NR20-CH(CO-)-(-(CH2)pNR20CONR20(CH2)P-CH(CO-)-NR20-; R71 is H; lower alkyl; lower alkenyl; -(CH2)p(CHR6')sOR75; -(CH2)p(CHRδ')sSR75;
-(CH2)P(CHR6 ' )SNR33R34; -(CH2)p(CHR6 ' )sOCONR33R75 ; -(CH2)p(CHR6 ' )SNR20CONR33R82; -(CH2)0(CHR6l)sCOOR75; -(CH2)pCONR58R59; -(CH2)pPO(ORδ2)2; -(CH2)pS02R62; or
-(CH2)o-C6R67R68R69R70R76; R72 is H; lower alkyl; lower alkenyl; -(CH2)p(CHR6l)s0R85; or -(CH2)P(CHR6')5SR85; R73 is -(CH2)0R77; -(CH2).0(CH2)0R77; -(CH2)rS(CH2)0R77; or -(CH2)rNR20(CH2)0R77; R74 is -(CH2)PNR78R79; -(CH2)PNR77R80; -(CH2)PC(=NR80)NR78R79 ; -(CH2)PC(=NOR50)NR78R79; -(CH2)PC(=NNR78R79)NR78R79; -(CH2)PNR80C(=NR80)NR78R79; '
-(CH2)pN=C(NR78R80)NR79R80;-(CH2)pC6H4NR78R79; -(CH2)pC6H4NR77R80; -(CH2)pC6H4C(=NR80)NR78R79; -(CH2)pC6H4C(=NOR50)NR78R79; -(CH2)pC6H4C(=NNR78R79)NR78R79; -(CH2)pC6H4NR80C(=NR80)NR78R79; -(CH2)μC6H4N=C(NR78R80)NR79R80; -(CH2)rO(CH2)mNR78R79; -(CH2)rO(CH2)mNR77R80; -(CH2)rO(CH2)pC(=NR 0)NR78R79; -(CH2)rO(CH2)pC(=NOR50)NR78R79;
-(CH2)rO(CH2)pC(=NNR78R79)NR78R79; -(CH2)rO(CH2)mNR80C(=NR80)NR78R79; -(CH2)rO(CH2)mN=C(NR78R80)NR79R80; -(CH2)rO(CH2)pC6H4CNR78R79; -(CH2)rO(CH2)pC6H4C(=NR80)NR78R7'J; -(CH2)rO(CH2)pC6H4C(=NOR50)NR78R79; -(CH2)rO(CH2)pC6H4C(=NNR78R79)NR78R79; -(CH2)rO(CH2)pC6H4NR80C(=NR80)NR78R79; -(CH2)rS(CH2) NR78R79;
-(CH2)rS(CH2) ιNR77R80;-(CH2)-S(CH2)pC(=NR80)NR78R79; -(CH2)rS(CH2)pC(=NOR50)NR78R79; -(CH2)rS(CH2)pC(=NNR78R79)NR78R79; -(CH2)rS(CH2)mNR80C(=NR80)NR78R79; -(CH2)rS(CH2)mN=C(NR78R8O)NR79R80; -(CH2)rS(CH2)pC6H4CNR78R79; -(CH2)rS(CH2)pC6H4C(=NR80)NR78R79; -(CH2)rS(CH2)pC6H4C(=NOR50)NR78R79; -(CH2)rS(CH2)pC6H4C(=NNR78R79)NR78R79;
-(CH2)rS(CH2)pC6H4NR80C(=NR80)NR78R79; -(CH2)pNR80COR64; -(CH2)pNR80COR77; -(CH2)PNR80CONR78R79; or -(CH2)PC6H4NR80CONR78R79; R75 is lower alkyl; lower alkenyl; or aryl-lower alkyl;
R33 and R75 taken together can fonn: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-;
R7S and R82 taken together can fonn: -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or R76 is H; lower alkyl; lower alkenyl; aryl-lower alkyl; -(CH2)00R72; -(CH2)0SR72; -(CH2)0NR33R34; -(CH2)00C0NR33R75; -(CH2)oNR20CONR33R82; -(CH2)0COOR75; -(CH2)0CONR58R59; -(CH2)oPO(OR60)2; -(CH2)PS02R62; or -(CH2)oCOR64;
R77 is -C6R67R68R69R70R7δ; or a heteroaryl group of one of the formulae
H1 H2 H3 H4 H5
H6 H7 H8 H9 H10
H11 H12 H13 H14 H15
H16 H17 H18 H19 H20
H26 H27 H28 H29
H30 H31 H32 H33
H34 H35 H36 H37
H42 H43 H44 H45
H46 H47 H48 H49
R78 is H; lower alkyl; aryl; or aryl-lower alkyl;
R78 and R82 taken together can form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; R79 is H; lower alkyl; aryl; or aryl-lower alkyl; or
R78 and R79, taken together, can be -(CH2)2-7-; -(CH2)20(CH2)2-; or -(CH2)2NR57(CH2)2-;
R80 is H; or lower alkyl;
R8' is H; lower alkyl; or aryl-lower alkyl;
R82 is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl; R33 and R82 taken together can form: -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-, R83 is H, lower alkyl, aryl, or -NR78R79,
R84 is -(CH2)m(CHR61)sOH, -(CH2)pCONR78R79, -(CH2)PNR80CONR78R79, -(CH2)PC6H4CONR78R79, or -(CH2)PC6H4NR80CONR78R79, R85 is lower alkyl, or lower alkenyl,
with the proviso that in said chain of 12 α-amino acid residues Z the amino acid residues in positions 1 to 12 are
PI of type C or oftype D or of type E or of type F, or the residue is Pro, - P2 oftype D,
P3 of type C, or of type D, or the residue is Pro, P4 of type C, or of type D, or of type E,
P5 of type E, or of type D, or of type C, or of type F, or the residue is Gly or Pro, P6 of type E, or of type F or of formula -A-CO-, or the residue is Gly , - P7 of type C, or of type E or of type F or of formula -B-CO-,
P8 of type D, or of type C, or of type F, or the residue is Pro, P9 of type C, or of type E or of type D or of type F, P10 of type F, or of type D or of type C, or the residue is Pro, Pl l oftype E or of type D or of type C or of type F, and - P12 of type C or oftype D or of type E or of type F, or the residue is Pro, or
P4 and P9 and/or P2 and PI 1, taken together, can form a group of type H, and at P6 and P7 also D-isomers being possible, with the further proviso that the amino acid residue in P4 is of type C, and/or - the ammo acid residue in P5 is of type F, and/or the amino acid residue in P7 is of type C, and/or the amino acid residue in P8 is of type F, and/or the amino acid residue in P9 is of type C, and/or the amino acid residue in PI 0 is of type F, and/or - the amino acid residue in PI 1 is of type C or of type F,
and pharmaceutically acceptable salts thereof ! Compounds according to claim 1 wherein
is a group of formula (al) or (a2)
3 Compounds according to claim 2 wherein A is a group of one of the formulae Al to A69,
R1 is hydrogen or lower alkyl,
R2 is H, lower alkyl, lower alkenyl, -(CH2)mOR55 (where R55 is lower alkyl, or lower alkenyl), - CH2)mSR56 (where R5δ is lower alkyl, or lower alkenyl), -(CH2)mNR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mOCONR33R75 (where R33 is H, lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mNR20CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oN(R20)COR64(where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), (CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, or lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oPO(ORδ0)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy),
R3 is H, lower alkyl, lower alkenyl, -(CH2)mOR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)mSR56 (where R56 is lower alkyl, or lower alkenyl), -(CH2)mNR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 β; -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl),
-(CH2)mOCONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)nιNR20CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2-6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl) , -(CH2)oN(R20)COR64 (where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2 β; -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)0PO(OR60)2 (where Rδ0 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy)
R4 is H, lower alkyl, lower alkenyl, -(CH2)mOR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)mSR56 (where R5δ is lower alkyl, or lower alkenyl), -(CH2)mNR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mOCONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2_5-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mNR20CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 β-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mN(R20)COR64(where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl),
-(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, or lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 isH, or lower alkyl), -(CH2)oPO(ORδ0)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy)
R5 is lower alkyl, lower alkenyl, -(CH2)0OR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)0SR5δ (where R5δ is lower alkyl, or lower alkenyl), (CH2)0NR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)00C0NR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2-6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)0NR20CONR33R82 (where R20 is H, or lower lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oN(R20)COR64 (where R20 is H, or lower alkyl, R64 is alkyl, alkenyl, aryl, aryl-lower alkyl, or heteroaryl-lower alkyl), -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, or lower alkyl, or R58 and R59 taken together are -(CH )2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oPO(OR60)2 (where Rδ0 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy)
Rδ is H, lower alkyl, lower alkenyl, -(CH2)0OR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)0SR56 (where R56 is lower alkyl, or lower alkenyl), -(CH2)0NR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)0OCONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2-6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oNR20CONR33R82 (where R20 is H, or lower lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-,
-(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oN(R20)COR64 (where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, or lower alkyl, or R58 and R59 taken together are -(CH2)2 6; -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)0PO(OR60)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy),
R7 is lower alkyl, lower alkenyl, -(CH )qOR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)qSR56 (where R56 is lower alkyl, or lower alkenyl), -(CH2)qNR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)q0C0NR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2) -6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)qNR20CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)qN(R20)COR64(where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -(CH2)rCOOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)qCONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, or lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)rPO(OR60)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)rS02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy),
R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, -(CH2)0OR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)0SR56 (where R56 is lower alkyl, or lower alkenyl), -(CH2)0NR3 R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)0OCONR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20 is H; or lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl);
-(CH2)oN(R20)COR64 (where R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl);
-(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; or lower alkyl; or R58 and R59 taken together are -(CH2)2-6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or -(CH2)qC6H4R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy);
R9 is lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55 is lower alkyl; or lower alkenyl);
-(CH2)0SR56 (where R56 is lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)00C0NR33R75 (where
R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are
-(CH2)2-5-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl);
-(CH2)mNR20CONR33R82 (where R20 is H; or lower lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oN(R20)COR64(where
R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; or lower alkyl; or R58 and R59 taken together are -(CH2)2-6-; -(CH2)2θ(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or -(CH2)qC6H4R8 (where
R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy);
R10 is lower alkyl; lower alkenyl; -(CH2)o0R55 (where R55 is lower alkyl; or lower alkenyl);
-(CH2)0SR56 (where R56 is lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2.6-; -(CH2)20(CH2) -;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)0OCONR33R75 (where
R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are
-(CH2)2<-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H is or lower alkyl);
-(CH2)0NR20CONR33R82 (where R20 is H; or lower lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-; -(CH2)2θ(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oN(R20)COR64(where R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; lower alkyl; or R58 and R59 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)0PO(ORδo)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or -(CH2)qC6H4R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy);
R" is H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55 is lower alkyl; or lower alkenyl); -(CH2)mSR56 (where R56 is lower alkyl; or lower alkenyl); -(CH2)mNR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2_6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl);
-(CH2)„,OCONR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and
R75 taken together ar -(CH2)2-δ-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20 is H; or lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl);
-(CH2)mN(R20)COR64 (where R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl);
-(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; lower alkyl; or R58 and R59 taken together are -(CH2)2.6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or -(CH2)qC6H4R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy);
R12 is H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55 is lower alkyl; or lower alkenyl);
-(CH2)mSR56 (where R5δ is lower alkyl; or lower alkenyl); -(CH2)mNR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2.6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl);
-(CH2)mOCONR33R75 (where R33is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and
R75 taken together are -(CH2)2^-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where
R57 is H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20 is H; or lower lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl);
-(CH2)mN(R20)COR64 (where: R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl);
-(CH2)rCOOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)rCONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; or lower alkyl; or R58 and R59 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl);
-(CH2)rPO(ORδ0)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R 2 (where Rδ2 is lower alkyl; or lower alkenyl); or -(CH2)qC6H4R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy):
R13 is lower alkyl; lower alkenyl; -(CH2)qOR55 (where R55 isis lower alkyl; or lower alkenyl); -(CH2)qSR5δ (where R56 is lower alkyl; or lower alkenyl); -(CH2)qNR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)qOCONR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2_5-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)qNR20CONR33R82 (where R20 is H; or lower lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)qN(R20)COR64 (where: R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)rCOOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)qCONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; or lower alkyl; or R58 and R59 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)rPO(OR60)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)-S02R62 (where R62 is lower alkyl; or lower alkenyl); or (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy); R14 is H; lower alkyl; lower alkenyl; -(CH2)mOR55 (where R55 is lower alkyl; or lower alkenyl); -(CH2)mSR56 (where R56 is lower alkyl; or lower alkenyl); -(CH2)mNR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2_6-;
-(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)mOCONR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2-6-; -(CH2)2θ(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20 is H; or lower lower alkyl; R33 is H; or lower alkyl; or lower alkenyl is R82: H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20 is H; lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; or lower alkyl; or R58 and R59 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl);
-(CH2)0PO(OR60)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or -(CH2)qC6H R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy); R15 is lower alkyl; lower alkenyl; -(CH )00R55 (where R55 is lower alkyl; or lower alkenyl); -(CH2)0SR56 (where R56 is lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)0OCONR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)0NR20CONR33R82 (where R20 is H; or lower lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-;
-(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oN(R20)COR64 (where R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -NR20COlower alkyl (R20=H; or lower alkyl); being particularly favoured; -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); - (CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl; and R59 is H; lower alkyl; or R58 and R59 taken together are -(CHz ; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oPO(ORδ0)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or (CH2)qC6H4R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy); R16 is lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55 is lower alkyl; or lower alkenyl); -(CH2)0SR56 (where R5δ is lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)00C0NR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20 is H; or lower lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2) -6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oN(R20)COR64 (where R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; or lower alkyl; or R58 and R59 taken together are -(CH2)2-6-; -(CH2)2θ(CH2)2-; -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oPO(ORδ0)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or -(CH2)qC6H4R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy); and R17 is lower alkyl; lower alkenyl; -(CH2)qOR55 (where R55 is lower alkyl; or lower alkenyl); -(CH2)qSR56 (where R56 is lower alkyl; or lower alkenyl); -(CH2)qNR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)q0C0NR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2_5-; -(CH2)20(CH2) ; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)qNR20CONR33R82 (where R20 is H; or lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)qN(R20)CORδ4(where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -(CH2)rCOOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)qCONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or where R57 is H, or lower alkyl), -(CH2)rPO(OR60)2 (where R60 is lower alkyl, or lower alkenyl),
-(CH2)rS02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy)
4 Compounds according to claim 2 or 3 wherein A is a group of one of the formulae A5 (with R2 being H), A8, A22, A25, A38 (with R2 being H), A42, and A50
5 Compounds according to claim 4 wherem A is a group of formula
A8* wherein R20 is H or lower alkyl, and R64 is alkyl, alkenyl, aryl, aryl-lower alkyl, or heteroaryl-lower alkyl
6 Compounds according to claim 5 wherein R64 is n-hexyl, n-heptyl, 4-(phenyl)benzyl, diphenylmethyl, 3-amιno-propyl, 5-amιno-pentyl, methyl, ethyl, isopropyl, isobutyl, n-propyl, cyclohexyl, cyclohexylmethyl, n-butyl, phenyl, benzyl, (3-ιndolyl)methyl, 2-(3-ιndolyl)ethyl, (4- phenyl)phenyl, or n-nonyl
7 Compounds according to claim 2 wherein A is a group of one of the formulae A70 to A 104, R20 is H, or lower alkyl,
R18 is lower alkyl, R19 is lower alkyl, lower alkenyl, -(CH2)pOR55 (where R55 is lower alkyl, or lower alkenyl),
-(CH2)PSR56 (where R56 is lower alkyl, or lower alkenyl), -(CH2)PNR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)pOCONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)PNR20CONR33R82 (where R20 is H, or lower lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)PN(R20)COR64 (where: R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); (CH2)pCOOR57 (where R57: lower alkyl; or lower alkenyl); (CH2)pCONR58R59 (where R58 is lower.alkyl; or lower alkenyl; and R59 is H; or lower alkyl; or R58 and R59 taken together are -(CH2)2_5-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oPO(OR60)2 (where Rδ0 is lower alkyl; or lower alkenyl); -(CH2)pS02R62 (where R62 is lower alkyl; or lower alkenyl); or (CH2)AH4R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy); R2' is H; lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55 is lower alkyl; or lower alkenyl); -(CH2)0SR56 (where R56 is lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl) ; -(CH2)00C0NR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20 is H; or lower lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oN(R20)COR64 (where: R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl; and R59 is H; lower alkyl; or R58 and R59 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)0PO(ORδo)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or -(CH2)qC6H4R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy);
R22 is lower alkyl; lower alkenyl; -(CH2)0OR55 (where R55 is lower alkyl; or lower alkenyl); -(CH2)0SR5δ (where R56 is lower alkyl; or lower alkenyl); -(CH2)0NR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)o0C0NR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oNR20CONR33R82 (where R20 is H; or lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-; -(CH2)2θ(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oN(R20)COR64(where R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl; and R59 is H; lower alkyl; or R58 and R59 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)0PO(ORδ0)2 (where Rδ0 is lower alkyl; or lower alkenyl); -(CH2)0S02Rδ2 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF, lower alkyl, lower alkenyl, or lower alkoxy),
R23 is H, lower alkyl, lower alkenyl, -(CH2)00R55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)0SR56 (where R56 is lower alkyl, or lower alkenyl), -(CH2)0NR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)0OCONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oNR 0CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-,
-(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oN(R20)COR54 (where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -NR20COlower alkyl (R20=H, or lower alkyl) being particularly favoured, -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oPO(OR60)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy), R24 is lower alkyl, lower alkenyl, -(CH2)0OR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)0SR5δ (where R56 is lower alkyl, or lower alkenyl), -(CH2)0NR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6; -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)0OCONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2-6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oNR20CONR33R82 (where R20 is H, or lower lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR"(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oN(R20)COR64 (where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -NR20COlower alkyl (R20=H , or lower alkyl) being particularly favoured, -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR5 R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2-6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oPO(OR60)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy), R25 is H, lower alkyl, lower alkenyl, -(CH2),„OR55 (where R55 is lower alkyl, or lower alkenyl),
-(CH2) NR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2<-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mOCONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2^-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR"(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mNR20CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2.6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)rnN(R20)COR64 (where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl),
-(CH2)oPO(OR60)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy), R δ is H, lower alkyl, lower alkenyl, -(CH2)mOR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)mNR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mOCONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2-5-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)nιNR20CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mN(R20)COR64 (where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl),
-(CH2)oPO(OR60)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy), or, alternatively, R25 and R26 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR34(CH2)2-, R27 is H, lower alkyl, lower alkenyl, -(CH2)0OR55 (where R55 is lower alkyl, or lower alkenyl),
-(CH2)0SR5δ (where R56 is lower alkyl, or lower alkenyl), -(CH2)0NR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)0OCONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oNR20CONR33R82 (where R20 is H, or lower lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2---, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oN(R20)COR64 (where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR5 R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2<-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or
-(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oPO(ORδ0)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy), R28 is lower alkyl, lower alkenyl, -(CH2)0OR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)0SR5δ (where R5δ is lower alkyl, or lower alkenyl), -(CH2)0NR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)00CONR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2-6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oNR20CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2-6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)0N(R20)CORδ (where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oPO(OR60)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)qC6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy), and R29 is lower alkyl, lower alkenyl, -(CH )0OR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)0SR56 (where R5δ is lower alkyl, or lower alkenyl), -(CH2)0NR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)00C0NR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2 6-, -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR5 (CH2)2-, where R57 is H, or lower alkyl), -(CH2)oNR20CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6; -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oN(R20)COR64(where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -NR20COlower-alkyl (R20=H, or lower alkyl) being particularly favoured, -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H; or lower alkyl); -(CH2)0PO(OR60)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or -(CH2)-C6H4R8 (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy).
8. Compounds according to claim 7 wherein R23, R24 and R29 are -NR20-CO-lower alkyl where R20 is H; or lower alkyl.
9. Compounds according to claim 7 or 8 wherein A is a group of one of the formulae A74 (with R22 being H); a75; A76; A77 (with R22 being H); A78; and A79.
10. Compounds according to any one of claims 2 to 9 wherein B is a group of formula -N NRR2200CCHH((RR7711))-- oorr aann eennaannttiioommeerr < of one of the groups A5 (with R2 being H); A8; A22; A25; A38 (with R2 being H); A42; A47; and A50.
11. Compounds according to claim 10 wherein B-CO is Ala; Arg; Asn; Cys; Gin; Gly; His; He;
Leu; Lys; Met; Phe; Pro; Ser; Thr; Trp; Tyr; Val; Cit; Orn; tBuA; Sar; t-BuG; 4AmPhe; 3AmPhe;
2AmPhe; Phe(mC(NH2)=NH; Phe(pC(NH2)=NH; Phe(mNHC (NH2)=NH; Phe(pNHC (NH2)=NH;
Phg; Cha; C4al; C5al; Nle; 2-Nal; 1-Nal; 4C1-Phe; 3C1-Phe; 2C1-Phe; 3,4Cl2Phe; 4F-Phe; 3F-Phe; 2F-
Phe; Tic; Thi; Tza; Mso; AcLys; Dpr; A2Bu; Dbu; Abu; Aha; Aib; Y(Bzl); Bip; S(Bzl); T(Bzl); hCha; hCys; hSer, hArg; hPhe; Bpa; Pip; OctG; MePhe; MeNle; MeAla; Melle; MeVal; or MeLeu.
12. Compounds according to claim 10 or 11 wherein B is a group, having (L)-confιguration, of formula
A8"
wherein R20 is H; or lower alkyl; and R64 is alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl.
13. Compounds according to claim 12 wherein R64 is n-hexyl; n-heptyl; 4-(phenyl)benzyl; diphenylmethyl, 3-amino-propyl; 5-amino-pentyl; methyl; ethyl; isopropyl; isobutyl; n-propyl; cyclohexyl; cyclohexylmethyl; n-butyl; phenyl; benzyl; (3-indolyl)methyl; 2-(3-indolyl)ethyl; (4- phenyl)phenyl; or n-nonyl.
14 Compounds according to claim 1 wherein
is a group of formula (bl) or (1), R1 is H, or lower alkyl, R20 is H, or lower alkyl, R30 is H, or methyl,
R3' is H, lower alkyl, lower alkenyl, -(CH2)pOR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)PNR33R34 (where R33 is lower alkyl, or lower alkenyl, R34 is H, or lower alkyl, or R33 and R34 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)P0C0NR33R75 (where R33 is H, or lower alkyl, or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)M-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or
-(CH2)2NR5 (CH2)2-, where R57 is H, or lower alkyl), -(CH2)PNR20CONR33R82 (where R20 is H, or lower alkyl, R33 is H, or lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R33 and R82 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)PN(R20)COR64 (where R20 is H, or lower alkyl, R64 is lower alkyl, or lower alkenyl), -(CH2)0COOR57 (where R57 is lower alkyl, or lower alkenyl), -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl, and R59 is H, lower alkyl, or R58 and R59 taken together are -(CH2)2 6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)oPO(ORδ0)2 (where R60 is lower alkyl, or lower alkenyl), -(CH2)0S02R62 (where R62 is lower alkyl, or lower alkenyl), or -(CH2)-C6H4R8 (where R8 is H, F, Cl, CF3, lower alkyl, lower alkenyl, or lower alkoxy), most preferably -CH2CONR58R59 (where R58 is H, or lower alkyl, and R59 is lower alkyl, or lower alkenyl), R32 is H, or methyl,
R33 is lower alkyl, lower alkenyl, -(CH2)mOR55 (where R55 is lower alkyl, or lower alkenyl), -(CH2)mNR34R63 (where R34 is lower alkyl, or lower alkenyl, R63 is H, or lower alkyl, or R34 and R63 taken together are -(CH2)M-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl), -(CH2)mOCONR75R82 (where R75 is lower alkyl, or lower alkenyl, R82 is H, or lower alkyl, or R75 and R82 taken together are -(CH2)2-6-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)mNR20CONR78R82 (where R20 is H; or lower alkyl; R78 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R78 and R82 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; lower alkyl; or R58 and R59 taken together are -(CH2)2_6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57: H; or lower alkyl); R34 is H; or lower alkyl; R35: isH; lower alkyl; lower alkenyl; (CH2)mOR55 (where R55: lower alkyl; or lower alkenyl); -(CH2)mNR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)M-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)„,OCONR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)mNR20CONR33R82 (where R20 is H; or lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)mN(R20)COR64 (where: R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl; or lower alkenyl; and R59 is H; lower alkyl; or R58 and R59 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); R36: lower alkyl; lower alkenyl; or aryl-lower alkyl;
R37 is H; lower alkyl; lower alkenyl; -(CH2)pOR55 (where R55 is lower alkyl; or lower alkenyl); -(CH2)pNR33R34 (where R33 is lower alkyl; or lower alkenyl; R34 is H; or lower alkyl; or R33 and R34 taken together are -(CH2)2_5-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl);- (CH2)p0C0NR33R75 (where R33 is H; or lower alkyl; or lower alkenyl; R75 is lower alkyl; or R33 and R75 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)PNR20CONR33R82 (where R20 is H; or lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2.6-; -(CH2)2θ(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)PN(R20)COR64 (where: R20 is H; or lower alkyl; R64 is lower alkyl; or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl; and R59 is H; lower alkyl; or R58 and R59 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)oPO(OR60)2 (where R60 is lower alkyl; or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alky; or lower alkenyl); or (where R8 is H; F; Cl; CF3; lower alkyl; lower alkenyl; or lower alkoxy); and R38 is H, lower alkyl; lower alkenyl, -(CH2)pOR55 (where R55 is lower alkyl; or lower alkenyl); -(CH2)PNR33R34 (where R33 is lower alkyl, or lower alkenyl; R34 is H; or lower alkyl, or R33 and R34 taken together sre -(CH2)2-6-; -(CH2)20(CH2)2-; -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl); -(CH2)pOCONR33R75 (where R33 is H; or lower alkyl; or lower alkenyl, R75 is lower alkyl, or R33 and R75 taken together are -(CH2)2.6-; -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-, where R57 is H, or lower alkyl); -(CH2)PNR20CONR33R82 (where R20 is H; or lower alkyl; R33 is H; or lower alkyl; or lower alkenyl; R82 is H; or lower alkyl; or R33 and R82 taken together are -(CH2)2-6-; -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H, or lower alkyl); -(CH2)PN(R20)COR64 (where R20 is H; or lower alkyl; R64 is lower alkyl, or lower alkenyl); -(CH2)0COOR57 (where R57 is lower alkyl; or lower alkenyl); -(CH2)0CONR58R59 (where R58 is lower alkyl, or lower alkenyl; and R59 is H; lower alkyl; or R58 and R59 taken together are -(CH2)2-6-; -(CH2)2θ(CH2)2-, -(CH2)2S(CH2)2-; or -(CH2)2NR57(CH2)2-; where R57 is H; or lower alkyl), -(CH2)oPO(OR60)2 (where R60 is lower alkyl, or lower alkenyl); -(CH2)0S02R62 (where R62 is lower alkyl; or lower alkenyl); or (where R8 is H; F; Cl; CF3; lower alkyl, lower alkenyl, or lower alkoxy).
15. Compounds according to claim 14 wherein R' is H, R20 is H; R30 is H; R31 is carboxymethyl, or lower alkoxycarbonylmethyl; R32 is H; R35 is methyl; R36 is methoxy, R37 is H and R38 is H
16 Compounds according to any one of claims 1 to 15 wherein the α-amino acid residues in positions 1 to 12 of the chain Z are-
PI : of type C or of type D or of type E or of type F; P2. oftype D; P3 of type C, - P4 of type E, or of type C;
P5 of type E, or of type F; P6: of type E, or of type F, or of formula -A-CO-; P7: of type E, or of type F, or of formula -B-CO-; P8- oftype D, or of type C, or of Type F; - P9 of type C, or of type E,
P10- of type F, or of type D, or of type C, PI 1 - of type D, or of type C, or of type F, P12: of type C or of type D or of type E or of type F, at P6 and P7 also D-isomers being possible; with the proviso that the amino acid residue in position P4 is of type C; and/or the amino acid residue in position P5 is of type F; and/or the amino acid residue in position P8 is of type F; and/or the amino acid residue in position P9 is of type C; and/or the amino acid residue in position PIO is of type F; and/or the amino acid residue in position PI 1 is of type C or F.
17. Compounds according to claim 16 wherein the α-amino acid residues in positions 1 to 12 of the chain Z are:
PI: Arg; - P2: Tφ;
P3: Leu; P4: Lys or Val; P5: Lys; P6: Arg; - P7: Arg;
P8: Trp;
P9: Leu, Val or Lys; P10: Tyr, Thr or Gin; P 11 : Val, Leu, Tyr or Gin; and - P12: Arg; with the proviso that the amino acid residue in position P4 is Val; and/or the amino acid residue in position P9 is Leu or Val; and/or the amino acid residue in position P10 is Thr or Gin; and/or - the amino acid residue in position PI 1 is Val or Leu or Gin.
18. A compound of formula I according to claim 1 wherein the template is DPro-LPro and the amino acid residues in position 1 - 12 are:
PI: Arg; - P2: Trp;
P3: Leu;
P4: Lys;
P5: Lys;
P6: Arg; - P7: Arg;
P8: Trp; P9 Leu, PIO Tyr, Pl l Tyr, and P12 Arg
19 A compound of formula I according to claim 1 wherein the template is DPro-LPro and the amino acid residues m position 1 - 12 are
PI Arg,
P2 T , - P3 Leu,
P4 Lys,
P5 Lys,
P6 Arg,
P7 Arg, - P8 Tφ,
P9 Lys,
P10 Tyr,
Pl l Val, and
P12 Arg
20 A compound of formula I according to claim 1 wherein the template is DPro- Pro and the amino acid residues in position 1 - 12 are
PI Arg,
P2 Tφ, - P3 Leu,
P4 Lys,
P5 Lys,
P6 Arg,
P7 Arg, - P8 Tφ,
P9 Lys,
P10 Thr,
Pl l Tyr, and
P12 Arg
21 A compound of formula I according to claim 1 wherein the template is DPro-LPro and the amino acid residues in position 1 - 12 are PI Arg, P2 Tφ, - P3 Leu,
P4 Lys, P5 Lys, P6 Arg, P7 Arg, - P8 Tφ,
P9 Lys, P10 Gin, Pl l Tyr, and P12 Arg
22 A compound of fonnula I according to claim 1 wherein the template is DPro-LPro and the amino acid residues in position 1 - 12 are PI Arg, P2 Tφ, - P3 Leu,
P4 Val, P5 Lys, P6 Arg, P7 Arg, - P8 Tφ,
P9 Lys, P10 Tyr, Pl l Tyr, and P12 Arg
23 A compound of formula I according to claim 1 wherein the template is DPro-LPro and the amino acid residues in position 1 - 12 are
PI Arg,
P2 Tφ, - P3 Leu,
P4 Lys, - P5: Lys;
- P6: Arg
- P7: Arg
- P8: Tφ
P9: Val
: P10: Tyr
- Pl l: Tyr and
- P12: Arg
24. A compound of formula I according to claim 1 wherein the template is DPro- Pro and the amino acid residues in position 1 - 12 are:
- PI: Arg;
- P2: T ;
- P3: Leu;
- P4: Lys;
- P5: Lys;
- P6: Arg;
- P7: Arg;
- P8: T ;
- P9: Lys;
- P10: Tyr;
- Pl l : Gin; and
- P12: Arj
25. Enantiomers of the compounds of formulae I as defined in claim 1.
26. Compounds according to any one of claims 1 to 25 for use as therapeutically active substances.
27. Compounds according the claims 26 having selective antimicrobial activity being in particular against Pseudomonas aeruginosa or Acinetobacter.
28. A pharmaceutical composition containing a compound according to any one of claims 1 to 25 and a pharmaceutically inert carrier.
29. Compositions according to claim 28 in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary or inhalation administration. 30 Compositions according to claim 28 or 29 in form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebuhser or suppositories
31 The use of compounds according to any one of claims 1 to 25 for the manufacture of a medicament for treating or preventing infections or diseases related to such infections
32 The use according to claim 31 wherem said infections are related to respiratory diseases such as cystic fibrosis, emphysema and asthma, related to skin or soft tissue diseases such as surgical wounds, traumatic wounds or burn wounds, related to gastrointestinal diseases such as epidemic diarrhea, necrotizing enterocohtis or typhlitis, related to eye diseases such as keratitis or endophthalmitis, related to ear diseases such as otitis, related to CNS diseases such as brain abscess or meningitis, related to bone diseases such as osteochondπtis or osteomyelitis, related to cardiovascular diseases such as endocartitis or pericarditis, related to gastrounnal diseases such as epididymitis, prostatitis or urethntis, related to cancer, or related to HIV
33 The use of compounds according to any one of claims 1 to 25 as disinfectants or preservatives for foodstuffs, cosmetics, medicaments and other nutrient-containing materials
34 A process for the manufacture of compounds according to any one of claims 1-24 which process comprises
(a) coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that ammo acid which in the desired end-product is in position 5, 6 or 7, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected,
(b) removing the N-protecting group from the product thus obtained,
(c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position nearer the N-termmal amino acid residue, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected,
(d) removing the N-protecting group from the product thus obtained,
(e) repeating steps (c) and (d) until the N-terminal amino acid residue has been introduced, (f) coupling the product thus obtained with a compound of the general formula
°V0H x
Template wherein
is as defined above and X is an N-protecting group or, if
is to be group (al) or (a2), above, alternatively
(fa) coupling the product obtained in step (e) with an appropriately N-protected derivative of an amino acid of the general formula
HOOC-B-H III or HOOC-A-H IV wherein B and A are as defined above , any functional group which may be present in said N- protected amino acid denvative being likewise appropnately protected,
(fb) removing the N-protecting group from the product thus obtained, and (fc) coupling the product thus obtained with an appropriately N-protected derivative of an amino acid of the above general formula IV and, respectively, III, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected, (g) removing the N-protecting group from the product obtained in step (f) or (fc), (h) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 12, any functional group which may be present in said N-protected ammo acid derivative being likewise appropriately protected, (l) removing the N-protecting group from the product thus obtained,
(j) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position 12, any functional group which may be present said N-protected amino acid derivative being likewise appropriately protected, (k) removing the N-protecting group from the product thus obtained, (1) repeating steps (j) and (k) until all ammo acid residues have been introduced,
(m) if desired, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated,
(o) detaching the product thus obtained from the solid support,
(p) cychzing the product cleaved from the solid support,
(q) if desired, forming one or two interstrand lιnkage(s) between side-chams of appropriate amino acid residues at opposite positions of the β-strand region,
(r) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule, and
(s) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt
35 A process for the manufacture of compounds according to any one of claims 1 -24 which process comprises (a') coupling an appropriately functionalized solid support with a compound of the general formula
Template wherein
°
Template is as defined above and X is an N-protecting group or, if
is to be group (al) or (a2), above, alternatively (a'a) coupling said appropriately functionalized solid support with an appropnately N- protected derivative of an amino acid of the general formula
HOOC-B-H III or HOOC-A-H IV wherein B and A are as defined above , any functional group which may be present in said N- protected ammo acid derivative being likewise appropnately protected, (a"b) removing the N-protecting group from the product thus obtained, and (a'c) coupling the product thus obtained with an appropriately N-protected derivative of an amino acid of the above general formula IV and, respectively, III, any functional group which may be present in said N-protected ammo acid derivative being likewise appropriately protected,
(b') removing the N-protecting group from the product obtained in step (a') or (a'c),
(c') coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 12, any functional group which may be present in said N-protected ammo acid derivative being likewise appropriately protected,
(d') removing the N-protecting group from the product thus obtained,
(e') coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected,
(f ) removing the N-protecting group from the product thus obtained,
(g') repeating steps (e') and (f ) until all amino acid residues have been introduced,
(h') if desired, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated,
0') detaching the product thus obtained from the solid support,
0') cychzing the product cleaved from the solid support,
(k') if desired forming one or two interstrand hnkage(s) between side-chains of appropriate amino acid residues at opposite positions of the β-strand region, (l1) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule, and
(m') if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the conesponding free compound of formula I or into a different, pharmaceutically acceptable, salt
36 A modification of the process of claim 34 or 35 for the manufacture of compounds according to claim 25 in which enantiomers of all chiral starting materials are used
EP02779268A 2002-08-20 2002-08-20 Template-fixed peptidomimetics with antibacterial activity Expired - Lifetime EP1532164B1 (en)

Applications Claiming Priority (1)

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CN105111280B (en) * 2005-02-17 2020-01-24 波利弗尔有限公司 Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity
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WO2007079597A1 (en) * 2006-01-16 2007-07-19 Polyphor Ltd. Template - fixed peptidomimetics with antimicrobial activity
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US20130123196A1 (en) * 2011-08-31 2013-05-16 New York University Thioether-, ether-, and alkylamine-linked hydrogen bond surrogate peptidomimetics
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NZ712739A (en) * 2013-03-30 2021-07-30 Polyphor Ag Beta-hairpin peptidomimetics
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US7582604B2 (en) 2009-09-01
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CA2496215A1 (en) 2004-03-04
CN1688600A (en) 2005-10-26
AU2002342618C1 (en) 2008-10-30
JP4221368B2 (en) 2009-02-12
US20050239693A1 (en) 2005-10-27
WO2004018503A1 (en) 2004-03-04
BRPI0215855B1 (en) 2016-12-13
AU2002342618B2 (en) 2007-12-20
HK1081561A1 (en) 2006-05-19
JP2006513981A (en) 2006-04-27
US20100056432A1 (en) 2010-03-04
AU2002342618A1 (en) 2004-03-11
CA2496215C (en) 2013-07-16
CN1688600B (en) 2010-04-28
AR043678A1 (en) 2005-08-10

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